Molecular analysis of T-cell Acute Lymphoblastic Leukemia arising after Essential Thrombocythemia foreshadows a distinct clonal route for lymphoid blast crisis in Philadelphia-negative chronic myeloproliferative neoplasm: a case report with literary review

Molecular analysis of T-cell Acute Lymphoblastic Leukemia arising after Essential Thrombocythemia foreshadows a distinct clonal route for lymphoid blast crisis in Philadelphia-negative chronic myeloproliferative neoplasm: a case report with literary review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Molecular analysis of T-cell Acute Lymphoblastic Leukemia arising after Essential Thrombocythemia foreshadows a distinct clonal route for lymphoid blast crisis in Philadelphia-negative chronic myeloproliferative neoplasm: a case report with literary review Francesco Grimaldi, Mara Memoli, Simona Avilia, Roberta Russo, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6232501/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 May, 2025 Read the published version in Annals of Hematology → Version 1 posted 9 You are reading this latest preprint version Abstract progression to acute myeloid leukemia is a well-known complication of classical philadelphia-negative chronic myeloproliferative neoplasms, but less frequently disease progression to Acute Lymphoblastic Leukemia has been documented too. A molecular explanation for this rare phenomenon is missing. However the clonal haematopoiesis mostly present in these patients may work as seeding soil for a second neoplastic disease. Molecular results from this case study of a secondary acute lymphoblastic leukemia presenting after Essential Thrombocythemia support this hypothesis. In this contest secondary Acute Lymphoblastic Leukemia should not be considered as a real blast crisis, but rather as a second cancer determined by a different clonal route. Given the unique features of this case, a review of the published cases of MPN transforming to acute lymphoblastic leukemia available in literature is provided in the article. secondary Acute Lymphoblastic Leukemia blast crisis clonal hematopoiesis Figures Figure 1 Figure 2 INTRODUCTION Progression to acute myeloid leukemia (AML) is a well-known complication of classic Philadelphia-negative chronic myeloproliferative neoplasms (MPN) such as Polycythaemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF)[ 1 ]. Frequency of evolution to AML is highest in PMF, where is estimated about 10–20% at 10 years, followed by PV, where is about 2.3% at 10 years and 7.9% at 20 years, and finally in ET, where transformation risk is expected to be less than 3% at 10 years, mainly related to cases classifiable as prefibrotic PMF [ 2 , 3 , 4 ]. Currently, JAK2, CALR and MPL mutations are considered to play a pivotal role as driver events in the disease pathogenesis [ 5 ], while leukemic evolution is commonly associated with accumulation of additional mutations in different myeloid cancer genes, such as RUNX1, ASXL1, IDH2, TP53, with an increasing clonal complexity and heterogeneity of hematopoietic stem cell (HSC) compartment [ 6 , 7 ]. Less frequently in MPNs disease progression to Acute Lymphoblastic Leukemia (sALL) has been documented [ 8 ]. Due to paucity of molecular and clinical data available [ 9 , 10 ], mechanism of lineage switch from a chronic myeloid disease to a lymphoid blast crisis remains elusive. However, given that most of sALL have been associated with B-lineage disease and JAK2 positivity [ 9 , 10 ], and that JAK2 mutation has been detected in B/NK/T-lymphoid precursors from PV and PMF patients [ 11 , 12 ], it has been speculated that the activity of JAK2 tyrosine kinase in a common myelo-lymphoid CD34 + progenitor may play a causative role for this condition. Nevertheless, some reports [ 13 , 14 ], have clearly showed how sALL could present mutations clonally distinct from the previous MPN diagnosis. In according with these observations, here we present the case of a T-cell sALL diagnosed in a patient with JAK2-V617F-positive ET, where molecular analysis performed during the disease course clearly show a secondary JAK2-negative neoplastic outgrowth, and a potential different clonal route for the sALL diagnosed after the MPN phase. CASE DESCRIPTION In October 2012 a 62 year-old women was initially reviewed in our clinic for thrombocytosis; JAK2-V617F molecular test (Supplementary methods, S1) was positive on peripheral blood and bone marrow biopsy was consistent with a histological diagnosis of ET. Patient was started on hydroxyurea, and continued on it with good response and without thrombotic events until ten years later, when she was urgently admitted for high fever, fatigue and joint pain. Complete blood counts at time showed: Hgb 10,4 g/dl, WBC 20.680/mm3, PLT 23.000/mm3. Peripheral blood and bone marrow smear revealed lymphoid blast cells (80% and 95% respectively), with following surface markers at flow-cytometry analysis: CD45dim, DR-, CD34-, CD5+, CD7+, CD2+, CD8+, CD1a+, CD99+, CD10+, CD3-, cyCD3+/- (Supplementary methods, S3). According to EGIL classification, diagnosis of secondary cortical T-ALL was made (Fig. 1 a). No specific chromosomal abnormalities or mutations were detected by conventional cytogenetic and RT-PCR testing. Additionally, JAK2-V617F mutation on bone marrow became undetectable. With RT-PCR, a disease specific VγI-Jγ1.1 IGH sequence was identified for monitoring of minimal residual disease (MRD) (Supplementary methods, S1). Patient started induction chemotherapy according to NILG 10/07 ALL protocol [ 15 ], for elderly patients (Age > 65 years). Bone marrow evaluation performed after cycle 1, 3 and 5 of chemotherapy (Time point 1, 2, 3; see Fig. 1 b) showed complete remission (CR), with molecular MRD constantly negative (below < 1x10-4 level of test sensitivity). Interestingly, JAK2-V617F mutation was again detectable in the bone marrow, with an increase in allele burden of 23,7% at Tp2 and 29,9% at Tp3. Patient successfully completed the planned 6 cycles of chemotherapy and started maintenance therapy. Bone marrow evaluation performed after first and second year of maintenance confirmed the CR status, with no blast cells detected by flow-cytometry, and JAK2-V617F positivity with a stable allele burden of 22,7% and 31.4% respectively. To further analyse clonal origin of T-cell sALL, a Next-Generation-Sequencing (NGS) study with a 36 myeloid gene panel (Supplementary methods, S2) was performed on available cell previously collected at time of diagnosis of ET, at time of diagnosis of s-ALL, and during maintenance therapy (At first and second year). NGS analysis of these four samples revealed two missense mutations in DNMT3A gene, occurring on exon 21 (Leu819Arg; T2456 > G) and exon 22 respectively (Glu865Lys; G2593 > A), known to be pathogenic and related with clonal haematopoiesis (CH). Interestingly these two mutations were detectable at the time of ET diagnosis with a variant allele frequency (VAF) of 44.4% and 44%, showed an increased VAF level of 89 and 77% at the moment of diagnosis of T-ALL, and despite the intensive chemotherapy administered to the patient, returned to a quite stable VAF of 41.7% and 40.4%, and of 45.7% and 43.9%, respectively after the first and second year of maintenance (see Fig. 1 c). Finally, to assess penetrance of DNMT3A and JAK2 mutations in pre-leukemic HSC compartment, NGS analysis was performed on sorted B and T-lymphocytes in peripheral blood, even if only from peripheral blood collected at second year of maintenance (Supplementary methods, S2, S3). Very interestingly it wasn’t possible to identify any JAK2 mutation in CD3 + and CD19 + sorted lymphocytes, while DNMT3A mutations was identified in T-lymphocytes even if at a low allele frequency at limits of assay detection (VAF below 5%). DISCUSSION with LITERATURE REVIEW Different studies have reported the incidence of sALL after prior malignancies: a large SEER analysis [ 16 ] have indicated a frequency for sALL of 6.6% on all the new diagnosis of acute lymphoblastic leukemia in US. A lower incidence of 2.3% was reported by a retrospective series by Pagano et al [ 17 ] for GIMEMA, while Aldoss et al[ 18 ] more recently reported a 9.3% incidence from a single US institution. In all these series not more than 10% of cases are diagnosed after a primary hematological cancer, and diagnosis of sALL after MPN remains an anecdotical event. Given the unique features of this case, we conducted a literature review for published cases of MPN transforming to ALL. We searched PubMed using the following keywords: “acute lymphoblastic leukemia, myeloproliferative neoplasm, chronic myeloproliferative, essential thrombocythemia, polycythemia vera, myelofibrosis”. After removing reviews and other irrelevant papers, we identified a total of 31 patients reported in literature from 1978 to nowadays. The complete patient series including our case is presented in Table 1 with references. On a total of 31 identified patients, median time to leukemic transformation from initial diagnosis of MPN is of 10 years. In 15 patients a molecular analysis of MPN phase was available, with a JAK2V617F mutation identified in 66% of cases (10/15). Major part of patients (78%) showed a B-cell phenotype in leukemic transformation (24/31), and despite intensive chemotherapy, only 25% of patients resulted alive at reported follow-up. Prevalence of sALL incidence in JAK2-mutated MPN have stimulated the idea that a common JAK2-mutated myelo-lymphoid precursor could explain the origin of this condition, sustained by the experimental evidence that generally a low JAK2 allelic burden (3–5%) can be found both in B- and T-lymphocytes of MPN patients [ 10 , 11 ]. However, in our case JAK2-V617F canonical mutation disappeared at the sALL onset, and became again detectable after the patient obtained the CR, with an allele burden progressively increased during maintenance therapy. The disappearance of JAK2V617F in the moment of diagnosis, when the blast size in bone marrow is relevant, have been already described even with differently mutated MPN (CALR-mut or MPL-mut) (See Table 1 ) and strongly indicates that the lymphoid blast clonal growth is independent from the MPN founding mutations, as suggested in other two molecularly-detailed case reports [ 13 , 14 ]. Table 1 Summary of cases of MPN transformed into sALL reported in literature. Case no. Year Age / gender MPN subtype Molecular status MPN treatment Time to progression (years) s-ALL Phenotype Cytogenetics (of sALL) Clinical outcome Reference 1 1978 77 / M PV NA Phlebotomy, CHL 6 B-cell Normal Dead [ 19 ] 2 1980 61 / M PMF NA Oxymetholone, splenectomy 5 B-cell Aneuploid Dead [ 20 ] 3 1980 53 / F PPV-MF NA Phlebotomy 18 Burkitt’s NA Dead [ 20 ] 4 1986 74 / M PV NA P32, Bu, CHL, BCNU 6 Null NA Dead [ 21 ] 5 1987 42 / M PV NA P32, Bu 10 Null Del 6q, +8 Dead [ 22 ] 6 1987 20 / M PV NA P32, Bu 10 T-cell NR Dead [ 22 ] 7 1988 68 / F PV NA P32, Bu, CHL 25 B-cell Complex Dead [ 23 ] 8 1993 54 / F PV NA P32 11 B-cell t(9;22) Dead [ 24 ] 9 1994 76 / M PV NA BU 16 B-cell Diploid Dead [ 25 ] 10 1995 50 / M ET NA HU 3 B-cell Complex Alive [ 26 ] 11 1996 54 / F PV NA P32, HU 13 B-cell NA Alive [ 27 ] 12 1996 87 / F ET NA HU 1 T-cell NA NA [ 28 ] 13 1996 70 / F ET NA P32, HU 19 B-cell Diploid NA [ 29 ] 14 1999 63 / M PPV-MF NA P32, HU 6 B-cell NA Dead [ 30 ] 15 2005 53 / M PMF NA HU 2 B-cell NA Dead [ 31 ] 16 2012 56 / M PMF Neg HU 1 B-cell t(9;22), del 20q Dead [ 32 ] 17 2012 54 / M PPV-MF Exon 12* Phlebotomy 4 B-cell Diploid Dead [ 33 ] 18 2014 5 / F PV NA Phlebotomy 17 B-cell NA NA [ 34 ] 19 2014 67 / F ET V617F* HU 16 B-cell t(9;22) Dead [ 35 ] 20 2015 65/ M ET V617F NA 16 B-cell Del (9) (p13) NA [ 36 ] 21 2015 59 / M ET-MF V617F NA 10 B-cell Del 13q and 20q NA [ 36 ] 22 2015 72 / M PV V617F HU 3 B-cell Normal Alive [ 37 ] 23 2016 64 / F PV V617F HU 4 B-cell Normal Alive [ 38 ] 24 2016 65 / F ET CALR HU 3.5 B-cell Hyperdiploid Alive [ 39 ] 25 2017 69 / F ET CALR HU, anagrelide, ruxolitinib 26 B-cell t(1;19) Dead [ 40 ] 26 2017 66 / F PMF V617F HU, lena 11 B-cell Complex monosomal Dead [ 41 ] 27 2018 76 / M PPV-MF V617F* Phlebotomy, ruxolitinib 7 B-cell NA NA [ 42 ] 28 2020 62 / M PMF V617F Epo 3 T-cell i(17) Dead [ 43 ] 29 2021 49 / M ET MPL HU 10 T-cell Complex Alive [ 44 ] 30 2021 67 / F ET MPL* HU 13 B-cell t(9;22) NA [ 45 ] 31 2022 77 / F ET Triple-neg HU 2 B-cell NA Alive [ 46 ] 32 2024 62 / F ET V617F* HU 10 T-cell Normal Alive Current Case Table 1 : ET, essential thrombocythemia; PV, policythemia vera; PMF, primary myelofibrosis; PPV-MF, post-PV myelofibrosis; PET-MF, post-ET myelofibrosis; NA, not available in the report; HU, hydroxyurea; CHL, clorambucil; P32, Phosphorus-32; Bu, busulphan; *Mutation not detectable, or with VAF ≤ 5%, at leukemic transformation. JAK2-driven hemopoiesis re-expanded once the patient achieved CR, showing the ability of JAK2-mutated HSC to survive under stress conditions as ones given by chemotherapy, and as highlighted in several MPN disease models [ 47 , 48 ]. NGS analysis identified two DNMT3A gene mutations that were present at the time of diagnosis of ET, increased in VAF only at the diagnosis of T-cell sALL, and then remained relatively stable during the entire course of the patient monitoring. Several studies of tumoral DNA from T-lymphoproliferative neoplasm [ 49 , 50 ], and recently even from elderly patients with T-cell ALL [ 51 , 52 ], have clearly identified an increased incidence of myeloid gene mutations, such as DNMT3A and TET2, in leukemic cells, exactly how we’ve seen in our patient. Additionally, at the time of ET diagnosis, VAF of DMNT3a mutation (around 40%) was much higher than the JAK2V617F allelic burden (20,9%), suggesting that DNMT3a was the first to appear in the HSC compartment of our patient. This condition is concordant with experimental observations [ 53 ] that determined the mutations order in which the HSC can acquire canonical JAK2 mutation. In some cases, mutations in epigenetic regulators such as TET2 can be acquired before JAK2, and in these conditions the HSC compartment is completely dominated by TET2 single-mutant cells (TET2-first). NGS data from our patient are consistent with the TET2-first model of MPN (even if in our case the mutations involved a different epigenetic regulator as DNMT3a) and suggest that the HSC compartment was dominated by DNMT3a at the time of diagnosis of ET. Two other elements support this idea. Firstly, DNMT3a mutation has been detected at a very low level even in mature T-lymphocytes in our sorting experiment, suggesting its persistence in a hierarchically higher progenitor of HSC. Secondly, the DNMT3a mutation remained detectable in bone marrow during CR, similarly to what happen in AML patients, confirming their nature of CH mutations [ 54 , 55 ], Taken altogether these observations show that in our patient genomic changes in the early HSC given by DNMT3A mutation acted as CH that may have predisposed firstly, after emergence of JAK2 mutation in DNMT3a mutated cells, to the development of ET, and secondly, after the rare occurrence of a new second genetic hit that we’ve been not able to identify, to the development of T-cell sALL years after the previous diagnosis of MPN (Fig. 2 ). However, once chemotherapy cleared all the blast cells in the bone marrow, DNMT3a and JAK2 mutated HSC expanded again on normal hematopoiesis. Thus, these data are consistent with possibility of a distinct route for lymphoid blast crisis in MPNs, substantially independent from JAK2 (or CALR or MPL) mutation, but initiated from a common clonal background, as already observed in other conditions [ 56 , 57 ]. CONCLUSIONS Clonal dynamics tracked down from our study shed some lights on the mechanism of lymphoid blast crisis diagnosed in the contest of MPN and support the hypothesis that the clonal haematopoiesis mostly present in these patients may work as seeding soil for a second neoplastic disease. In this contest sALL observed after Philadelphia-negative MPN should not be considered as a real blast crisis, but rather as a second cancer determined by a different neoplastic route that share the same clonal starting point with the underlying MPN. Despite the rarity of these cases, additional genomic studies, possibly at a single-cell-level, will be needed to clearly understand and finally assess the origin of this rare phaenomenon. Declarations No funding was received to assist with the preparation of this manuscript. The authors declare that they have no conflict of interest in connection with the submitted article. Written informed consent for publication of clinical and biological data was obtained from patient, and approved by institutional ethical board. Treatment study was conducted in accordance with the Declaration of Helsinki. A copy of the consent form is available for review by the Editor of this journal. Data-sharing statement Please email the corresponding author to obtain original data. Author Contribution FG designed the study and wrote the manuscript. FG, MM, SA, RR participated in patient care. MM, GS, SE, RV, and BI performed laboratory tests, data interpretation and data analysis. 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Distinct patterns of clonal evolution in patients with concurrent myelo- and lymphoproliferative neoplasms. Blood. 2018 Nov 15;132(20):2201-2205. Additional Declarations No competing interests reported. Supplementary Files SupplementaryMethods.docx Cite Share Download PDF Status: Published Journal Publication published 22 May, 2025 Read the published version in Annals of Hematology → Version 1 posted Editorial decision: Revision requested 08 Apr, 2025 Reviews received at journal 08 Apr, 2025 Reviews received at journal 04 Apr, 2025 Reviewers agreed at journal 26 Mar, 2025 Reviewers agreed at journal 25 Mar, 2025 Reviewers invited by journal 25 Mar, 2025 Editor assigned by journal 25 Mar, 2025 Submission checks completed at journal 25 Mar, 2025 First submitted to journal 15 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6232501","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":434351169,"identity":"74b024b7-f40c-4902-8bc0-912e0afcf2ab","order_by":0,"name":"Francesco Grimaldi","email":"data:image/png;base64,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","orcid":"","institution":"University of Naples Federico II","correspondingAuthor":true,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Grimaldi","suffix":""},{"id":434351171,"identity":"43a2494a-a669-4c98-831a-ab128fcb18bf","order_by":1,"name":"Mara Memoli","email":"","orcid":"","institution":"University of Naples Federico II","correspondingAuthor":false,"prefix":"","firstName":"Mara","middleName":"","lastName":"Memoli","suffix":""},{"id":434351173,"identity":"f12de434-c382-4655-90cb-c316cddc126e","order_by":2,"name":"Simona Avilia","email":"","orcid":"","institution":"University of Naples Federico II","correspondingAuthor":false,"prefix":"","firstName":"Simona","middleName":"","lastName":"Avilia","suffix":""},{"id":434351175,"identity":"78be2c31-9708-4990-89df-0aeb3be33efd","order_by":3,"name":"Roberta Russo","email":"","orcid":"","institution":"University of Naples Federico II","correspondingAuthor":false,"prefix":"","firstName":"Roberta","middleName":"","lastName":"Russo","suffix":""},{"id":434351177,"identity":"c65e003b-f28d-4cb6-bcc5-5ed85bf42023","order_by":4,"name":"Giulia Scalia","email":"","orcid":"","institution":"Ceinge Biotecnologie Avanzate (Italy)","correspondingAuthor":false,"prefix":"","firstName":"Giulia","middleName":"","lastName":"Scalia","suffix":""},{"id":434351179,"identity":"92e66af7-f673-4f9a-9ceb-6d3dc427f687","order_by":5,"name":"Roberta Visconti","email":"","orcid":"","institution":"Ceinge Biotecnologie Avanzate (Italy)","correspondingAuthor":false,"prefix":"","firstName":"Roberta","middleName":"","lastName":"Visconti","suffix":""},{"id":434351181,"identity":"472d2be8-0d3f-4a28-bed5-1d30c8c96595","order_by":6,"name":"Santa Errichiello","email":"","orcid":"","institution":"Ceinge Biotecnologie Avanzate (Italy)","correspondingAuthor":false,"prefix":"","firstName":"Santa","middleName":"","lastName":"Errichiello","suffix":""},{"id":434351182,"identity":"06b5a056-f047-45b7-a00e-c7d7b62444d9","order_by":7,"name":"Barbara Izzo","email":"","orcid":"","institution":"University of Naples Federico II","correspondingAuthor":false,"prefix":"","firstName":"Barbara","middleName":"","lastName":"Izzo","suffix":""},{"id":434351183,"identity":"80c9fa4f-8150-433a-a559-281751ddcc98","order_by":8,"name":"Fabrizio Pane","email":"","orcid":"","institution":"University of Naples Federico II","correspondingAuthor":false,"prefix":"","firstName":"Fabrizio","middleName":"","lastName":"Pane","suffix":""}],"badges":[],"createdAt":"2025-03-15 11:23:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6232501/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6232501/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00277-025-06404-z","type":"published","date":"2025-05-22T15:57:17+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":80050533,"identity":"4ce6c4cd-88af-4d38-966c-3cda6006b69d","added_by":"auto","created_at":"2025-04-07 10:20:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":161436,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003ea:\u003c/strong\u003e\u003c/em\u003e\u003cem\u003eDiagnosis of secondary T-ALL (sALL). \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eFig.1b: \u003c/strong\u003e\u003c/em\u003e\u003cem\u003eNILG-ALL 10/07 regimen. IND=induction, C=consolidation, HD=high dose chemotherapy, Mant=maintenance. VCR=vincristine, IDA=idarubicin, Dexa=Dexamethasone, Ctx=cyclophosphamide, 6MP=6-mercaptopurin, MTX=Methotrexathe, PDN=prednisone. Black arrow=MRD sampling, Red arrow=JAK2 allelic burden, Blue arrow=NGS sampling. \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eFig.1c: \u003c/strong\u003e\u003c/em\u003e\u003cem\u003emutations kinetics observed from ET diagnosis trough sALL treatment.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6232501/v1/fb7bc14b929c00375687b7bd.png"},{"id":80052151,"identity":"c30d7e09-a3b5-48c8-8a3d-0d4c65c59d23","added_by":"auto","created_at":"2025-04-07 10:36:59","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":52218,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eET originates from clonal haematopoiesis when JAK2V617F mutation occurred on DNMT3a mutated cells. Years after, a new genetic hit selects a s-ALL clone and drives leukemia expansion over JAK2-mutated cells. After chemotherapy, under stress conditions, DNMT3a+ JAK2+ clone re-expanded over polyclonal haematopoiesis, with increasing allele burden.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6232501/v1/7dad52a030497d29d0274d7b.png"},{"id":83459989,"identity":"755e268a-935c-4471-8c0c-28a065bafcca","added_by":"auto","created_at":"2025-05-26 16:07:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1128744,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6232501/v1/3134d2f7-e485-4162-adc0-8e0c4113816f.pdf"},{"id":80050529,"identity":"bfb58a55-0f72-4280-8df5-056db83a1989","added_by":"auto","created_at":"2025-04-07 10:20:59","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18293,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMethods.docx","url":"https://assets-eu.researchsquare.com/files/rs-6232501/v1/4c9a90acd1b8b32531e40491.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Molecular analysis of T-cell Acute Lymphoblastic Leukemia arising after Essential Thrombocythemia foreshadows a distinct clonal route for lymphoid blast crisis in Philadelphia-negative chronic myeloproliferative neoplasm: a case report with literary review","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eProgression to acute myeloid leukemia (AML) is a well-known complication of classic Philadelphia-negative chronic myeloproliferative neoplasms (MPN) such as Polycythaemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF)[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Frequency of evolution to AML is highest in PMF, where is estimated about 10\u0026ndash;20% at 10 years, followed by PV, where is about 2.3% at 10 years and 7.9% at 20 years, and finally in ET, where transformation risk is expected to be less than 3% at 10 years, mainly related to cases classifiable as prefibrotic PMF [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Currently, JAK2, CALR and MPL mutations are considered to play a pivotal role as driver events in the disease pathogenesis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], while leukemic evolution is commonly associated with accumulation of additional mutations in different myeloid cancer genes, such as RUNX1, ASXL1, IDH2, TP53, with an increasing clonal complexity and heterogeneity of hematopoietic stem cell (HSC) compartment [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLess frequently in MPNs disease progression to Acute Lymphoblastic Leukemia (sALL) has been documented [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Due to paucity of molecular and clinical data available [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], mechanism of lineage switch from a chronic myeloid disease to a lymphoid blast crisis remains elusive. However, given that most of sALL have been associated with B-lineage disease and JAK2 positivity [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], and that JAK2 mutation has been detected in B/NK/T-lymphoid precursors from PV and PMF patients [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], it has been speculated that the activity of JAK2 tyrosine kinase in a common myelo-lymphoid CD34\u0026thinsp;+\u0026thinsp;progenitor may play a causative role for this condition. Nevertheless, some reports [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], have clearly showed how sALL could present mutations clonally distinct from the previous MPN diagnosis. In according with these observations, here we present the case of a T-cell sALL diagnosed in a patient with JAK2-V617F-positive ET, where molecular analysis performed during the disease course clearly show a secondary JAK2-negative neoplastic outgrowth, and a potential different clonal route for the sALL diagnosed after the MPN phase.\u003c/p\u003e"},{"header":"CASE DESCRIPTION","content":"\u003cp\u003eIn October 2012 a 62 year-old women was initially reviewed in our clinic for thrombocytosis; JAK2-V617F molecular test (Supplementary methods, S1) was positive on peripheral blood and bone marrow biopsy was consistent with a histological diagnosis of ET. Patient was started on hydroxyurea, and continued on it with good response and without thrombotic events until ten years later, when she was urgently admitted for high fever, fatigue and joint pain. Complete blood counts at time showed: Hgb 10,4 g/dl, WBC 20.680/mm3, PLT 23.000/mm3. Peripheral blood and bone marrow smear revealed lymphoid blast cells (80% and 95% respectively), with following surface markers at flow-cytometry analysis: CD45dim, DR-, CD34-, CD5+, CD7+, CD2+, CD8+, CD1a+, CD99+, CD10+, CD3-, cyCD3+/- (Supplementary methods, S3). According to EGIL classification, diagnosis of secondary cortical T-ALL was made (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). No specific chromosomal abnormalities or mutations were detected by conventional cytogenetic and RT-PCR testing. Additionally, JAK2-V617F mutation on bone marrow became undetectable. With RT-PCR, a disease specific VγI-Jγ1.1 IGH sequence was identified for monitoring of minimal residual disease (MRD) (Supplementary methods, S1). Patient started induction chemotherapy according to NILG 10/07 ALL protocol [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], for elderly patients (Age \u0026gt; 65 years). Bone marrow evaluation performed after cycle 1, 3 and 5 of chemotherapy (Time point 1, 2, 3; see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb) showed complete remission (CR), with molecular MRD constantly negative (below \u0026lt; 1x10-4 level of test sensitivity). Interestingly, JAK2-V617F mutation was again detectable in the bone marrow, with an increase in allele burden of 23,7% at Tp2 and 29,9% at Tp3. Patient successfully completed the planned 6 cycles of chemotherapy and started maintenance therapy. Bone marrow evaluation performed after first and second year of maintenance confirmed the CR status, with no blast cells detected by flow-cytometry, and JAK2-V617F positivity with a stable allele burden of 22,7% and 31.4% respectively. To further analyse clonal origin of T-cell sALL, a Next-Generation-Sequencing (NGS) study with a 36 myeloid gene panel (Supplementary methods, S2) was performed on available cell previously collected at time of diagnosis of ET, at time of diagnosis of s-ALL, and during maintenance therapy (At first and second year). NGS analysis of these four samples revealed two missense mutations in DNMT3A gene, occurring on exon 21 (Leu819Arg; T2456 \u0026gt; G) and exon 22 respectively (Glu865Lys; G2593 \u0026gt; A), known to be pathogenic and related with clonal haematopoiesis (CH). Interestingly these two mutations were detectable at the time of ET diagnosis with a variant allele frequency (VAF) of 44.4% and 44%, showed an increased VAF level of 89 and 77% at the moment of diagnosis of T-ALL, and despite the intensive chemotherapy administered to the patient, returned to a quite stable VAF of 41.7% and 40.4%, and of 45.7% and 43.9%, respectively after the first and second year of maintenance (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). Finally, to assess penetrance of DNMT3A and JAK2 mutations in pre-leukemic HSC compartment, NGS analysis was performed on sorted B and T-lymphocytes in peripheral blood, even if only from peripheral blood collected at second year of maintenance (Supplementary methods, S2, S3). Very interestingly it wasn’t possible to identify any JAK2 mutation in CD3 + and CD19 + sorted lymphocytes, while DNMT3A mutations was identified in T-lymphocytes even if at a low allele frequency at limits of assay detection (VAF below 5%).\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION with LITERATURE REVIEW","content":"\u003cp\u003eDifferent studies have reported the incidence of sALL after prior malignancies: a large SEER analysis [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] have indicated a frequency for sALL of 6.6% on all the new diagnosis of acute lymphoblastic leukemia in US. A lower incidence of 2.3% was reported by a retrospective series by Pagano et al [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] for GIMEMA, while Aldoss et al[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] more recently reported a 9.3% incidence from a single US institution. In all these series not more than 10% of cases are diagnosed after a primary hematological cancer, and diagnosis of sALL after MPN remains an anecdotical event. Given the unique features of this case, we conducted a literature review for published cases of MPN transforming to ALL. We searched PubMed using the following keywords: “acute lymphoblastic leukemia, myeloproliferative neoplasm, chronic myeloproliferative, essential thrombocythemia, polycythemia vera, myelofibrosis”. After removing reviews and other irrelevant papers, we identified a total of 31 patients reported in literature from 1978 to nowadays. The complete patient series including our case is presented in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e with references.\u003c/p\u003e\u003cp\u003eOn a total of 31 identified patients, median time to leukemic transformation from initial diagnosis of MPN is of 10 years. In 15 patients a molecular analysis of MPN phase was available, with a JAK2V617F mutation identified in 66% of cases (10/15). Major part of patients (78%) showed a B-cell phenotype in leukemic transformation (24/31), and despite intensive chemotherapy, only 25% of patients resulted alive at reported follow-up. Prevalence of sALL incidence in JAK2-mutated MPN have stimulated the idea that a common JAK2-mutated myelo-lymphoid precursor could explain the origin of this condition, sustained by the experimental evidence that generally a low JAK2 allelic burden (3–5%) can be found both in B- and T-lymphocytes of MPN patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, in our case JAK2-V617F canonical mutation disappeared at the sALL onset, and became again detectable after the patient obtained the CR, with an allele burden progressively increased during maintenance therapy. The disappearance of JAK2V617F in the moment of diagnosis, when the blast size in bone marrow is relevant, have been already described even with differently mutated MPN (CALR-mut or MPL-mut) (See Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and strongly indicates that the lymphoid blast clonal growth is independent from the MPN founding mutations, as suggested in other two molecularly-detailed case reports [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of cases of MPN transformed into sALL reported in literature.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"11\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase no.\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYear\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge / gender\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMPN\u003c/p\u003e \u003cp\u003esubtype\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMolecular status\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMPN\u003c/p\u003e \u003cp\u003etreatment\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eTime to progression (years)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003es-ALL Phenotype\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCytogenetics\u003c/p\u003e \u003cp\u003e(of sALL)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eClinical outcome\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1978\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e77 / M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePV\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePhlebotomy, CHL\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1980\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61 / M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePMF\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOxymetholone, splenectomy\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAneuploid\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1980\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53 / F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePPV-MF\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePhlebotomy\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBurkitt’s\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1986\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74 / M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePV\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP32, Bu, CHL, BCNU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNull\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1987\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 / M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePV\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP32, Bu\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNull\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDel 6q, +8\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1987\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 / M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePV\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP32, Bu\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eT-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1988\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68 / F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePV\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP32, Bu, CHL\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eComplex\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1993\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 / F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePV\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP32\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003et(9;22)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e9\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1994\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76 / M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePV\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDiploid\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1995\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 / M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eET\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eComplex\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAlive\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e11\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1996\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 / F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePV\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP32, HU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAlive\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e12\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1996\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87 / F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eET\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eT-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e13\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1996\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70 / F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eET\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP32, HU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDiploid\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e14\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1999\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 / M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePPV-MF\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP32, HU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e15\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2005\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53 / M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePMF\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e16\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2012\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 / M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePMF\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNeg\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003et(9;22), del 20q\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e17\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2012\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 / M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePPV-MF\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eExon 12*\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePhlebotomy\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDiploid\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e18\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 / F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePV\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePhlebotomy\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e19\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67 / F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eET\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eV617F*\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003et(9;22)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e20\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65/ M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eET\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eV617F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDel (9) (p13)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e21\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59 / M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eET-MF\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eV617F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDel 13q and 20q\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e22\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72 / M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePV\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eV617F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAlive\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e23\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64 / F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePV\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eV617F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAlive\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e24\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65 / F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eET\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCALR\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.5\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eHyperdiploid\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAlive\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e25\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69 / F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eET\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCALR\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHU, anagrelide, ruxolitinib\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003et(1;19)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e26\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66 / F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePMF\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eV617F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHU, lena\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eComplex monosomal\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e27\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76 / M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePPV-MF\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eV617F*\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePhlebotomy,\u003c/p\u003e \u003cp\u003eruxolitinib\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e28\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62 / M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePMF\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eV617F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEpo\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eT-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ei(17)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e29\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49 / M\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eET\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMPL\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eT-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eComplex\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAlive\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e30\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67 / F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eET\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMPL*\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003et(9;22)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e31\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2022\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e77 / F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eET\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTriple-neg\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eB-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAlive\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e32\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2024\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62 / F\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eET\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eV617F*\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eT-cell\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAlive\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eCurrent Case\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e: \u003cb\u003eET, essential thrombocythemia; PV, policythemia vera; PMF, primary myelofibrosis; PPV-MF, post-PV myelofibrosis; PET-MF, post-ET myelofibrosis; NA, not available in the report; HU, hydroxyurea; CHL, clorambucil; P32, Phosphorus-32; Bu, busulphan; *Mutation not detectable, or with VAF ≤ 5%, at leukemic transformation.\u003c/b\u003e\u003c/p\u003e\u003cp\u003eJAK2-driven hemopoiesis re-expanded once the patient achieved CR, showing the ability of JAK2-mutated HSC to survive under stress conditions as ones given by chemotherapy, and as highlighted in several MPN disease models [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. NGS analysis identified two DNMT3A gene mutations that were present at the time of diagnosis of ET, increased in VAF only at the diagnosis of T-cell sALL, and then remained relatively stable during the entire course of the patient monitoring. Several studies of tumoral DNA from T-lymphoproliferative neoplasm [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e], and recently even from elderly patients with T-cell ALL [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e], have clearly identified an increased incidence of myeloid gene mutations, such as DNMT3A and TET2, in leukemic cells, exactly how we’ve seen in our patient. Additionally, at the time of ET diagnosis, VAF of DMNT3a mutation (around 40%) was much higher than the JAK2V617F allelic burden (20,9%), suggesting that DNMT3a was the first to appear in the HSC compartment of our patient. This condition is concordant with experimental observations [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e] that determined the mutations order in which the HSC can acquire canonical JAK2 mutation. In some cases, mutations in epigenetic regulators such as TET2 can be acquired before JAK2, and in these conditions the HSC compartment is completely dominated by TET2 single-mutant cells (TET2-first). NGS data from our patient are consistent with the TET2-first model of MPN (even if in our case the mutations involved a different epigenetic regulator as DNMT3a) and suggest that the HSC compartment was dominated by DNMT3a at the time of diagnosis of ET. Two other elements support this idea. Firstly, DNMT3a mutation has been detected at a very low level even in mature T-lymphocytes in our sorting experiment, suggesting its persistence in a hierarchically higher progenitor of HSC. Secondly, the DNMT3a mutation remained detectable in bone marrow during CR, similarly to what happen in AML patients, confirming their nature of CH mutations [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e],\u003c/p\u003e\u003cp\u003eTaken altogether these observations show that in our patient genomic changes in the early HSC given by DNMT3A mutation acted as CH that may have predisposed firstly, after emergence of JAK2 mutation in DNMT3a mutated cells, to the development of ET, and secondly, after the rare occurrence of a new second genetic hit that we’ve been not able to identify, to the development of T-cell sALL years after the previous diagnosis of MPN (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). However, once chemotherapy cleared all the blast cells in the bone marrow, DNMT3a and JAK2 mutated HSC expanded again on normal hematopoiesis. Thus, these data are consistent with possibility of a distinct route for lymphoid blast crisis in MPNs, substantially independent from JAK2 (or CALR or MPL) mutation, but initiated from a common clonal background, as already observed in other conditions [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e].\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eClonal dynamics tracked down from our study shed some lights on the mechanism of lymphoid blast crisis diagnosed in the contest of MPN and support the hypothesis that the clonal haematopoiesis mostly present in these patients may work as seeding soil for a second neoplastic disease. In this contest sALL observed after Philadelphia-negative MPN should not be considered as a real blast crisis, but rather as a second cancer determined by a different neoplastic route that share the same clonal starting point with the underlying MPN. Despite the rarity of these cases, additional genomic studies, possibly at a single-cell-level, will be needed to clearly understand and finally assess the origin of this rare phaenomenon.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cp\u003eNo funding was received to assist with the preparation of this manuscript. The authors declare that they have no conflict of interest in connection with the submitted article.\u003c/p\u003e \u003cp\u003eWritten informed consent for publication of clinical and biological data was obtained from patient, and approved by institutional ethical board. Treatment study was conducted in accordance with the Declaration of Helsinki. A copy of the consent form is available for review by the Editor of this journal.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eData-sharing statement\u003c/strong\u003e \u003cp\u003ePlease email the corresponding author to obtain original data.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eFG designed the study and wrote the manuscript. FG, MM, SA, RR participated in patient care. MM, GS, SE, RV, and BI performed laboratory tests, data interpretation and data analysis. FG, BI and FP reviewed and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSpivak JL. Myeloproliferative Neoplasms. N Engl J Med. 2017 Jun 1;376(22):2168-2181. \u003c/li\u003e\n\u003cli\u003eIurlo A, Cattaneo D, Gianelli U. Blast Transformation in Myeloproliferative Neoplasms: Risk Factors, Biological Findings, and Targeted Therapeutic Options. 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Blood. 2018 Nov 15;132(20):2201-2205.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"secondary Acute Lymphoblastic Leukemia, blast crisis, clonal hematopoiesis","lastPublishedDoi":"10.21203/rs.3.rs-6232501/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6232501/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eprogression to acute myeloid leukemia is a well-known complication of classical philadelphia-negative chronic myeloproliferative neoplasms, but less frequently disease progression to Acute Lymphoblastic Leukemia has been documented too. A molecular explanation for this rare phenomenon is missing. However the clonal haematopoiesis mostly present in these patients may work as seeding soil for a second neoplastic disease. Molecular results from this case study of a secondary acute lymphoblastic leukemia presenting after Essential Thrombocythemia support this hypothesis. In this contest secondary Acute Lymphoblastic Leukemia should not be considered as a real blast crisis, but rather as a second cancer determined by a different clonal route. Given the unique features of this case, a review of the published cases of MPN transforming to acute lymphoblastic leukemia available in literature is provided in the article.\u003c/p\u003e","manuscriptTitle":"Molecular analysis of T-cell Acute Lymphoblastic Leukemia arising after Essential Thrombocythemia foreshadows a distinct clonal route for lymphoid blast crisis in Philadelphia-negative chronic myeloproliferative neoplasm: a case report with literary review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-07 10:20:54","doi":"10.21203/rs.3.rs-6232501/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-08T15:57:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-08T15:41:01+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-04T08:37:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"36946168177199720241977615309062359465","date":"2025-03-26T14:04:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"53437017299224730676320555823652821304","date":"2025-03-25T15:12:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-25T14:13:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-25T06:49:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-25T06:48:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2025-03-15T11:17:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"20d14c91-56e0-4fe7-b07c-427cbd560d3b","owner":[],"postedDate":"April 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-26T16:00:25+00:00","versionOfRecord":{"articleIdentity":"rs-6232501","link":"https://doi.org/10.1007/s00277-025-06404-z","journal":{"identity":"annals-of-hematology","isVorOnly":false,"title":"Annals of Hematology"},"publishedOn":"2025-05-22 15:57:17","publishedOnDateReadable":"May 22nd, 2025"},"versionCreatedAt":"2025-04-07 10:20:54","video":"","vorDoi":"10.1007/s00277-025-06404-z","vorDoiUrl":"https://doi.org/10.1007/s00277-025-06404-z","workflowStages":[]},"version":"v1","identity":"rs-6232501","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6232501","identity":"rs-6232501","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}