CUX1–PDGFRA: a novel fusion in myeloid/lymphoid neoplasms with eosinophilia

CUX1–PDGFRA: a novel fusion in myeloid/lymphoid neoplasms with eosinophilia | 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 Case Report CUX1–PDGFRA: a novel fusion in myeloid/lymphoid neoplasms with eosinophilia Lei Wang, Yinghui Liu, Xiaoxia Chu, Jinyao Ning, Xiaoqian Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8357179/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Eosinophilic disorders are a heterogeneous group of neoplastic and non-neoplastic conditions, characterized by increased number of eosinophils in the peripheral blood and sometimes lead to eosinophil-driven organ damage and dysfunction. Myeloid/lymphoid neoplasms with eosinophilia and tyrosine-kinase fusion genes (MLN-TK) is a group of hematologic neoplasms resulting from the formation of abnormal fusion genes that encode constitutively activated tyrosine kinases. The FIP1L1-PDGFRA fusion gene is the most common genetic abnormality detected in MLN-TK and nine rarer PDGFRA partners have also been documented at the time of writing. A novel fusion gene CUX1-PDGFRA was identified in an adult male with myeloid/lymphoid neoplasms with eosinophilia and tyrosine-kinase fusion genes (MLN-TK) through targeted RNA sequencing. This is the eleventh partner gene fusions for PDGFRA in MLN-TK discovered so far. Given the exquisite responsiveness of PDGFRA fusions to imatinib, we recommended imatinib at a dose of 100mg daily to the patient. The therapeutic response and prognosis remains to be further observed. eosinophilia myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions PDGFRA CUX1 CUX1::PDGFRA imatinib Figures Figure 1 Introduction PDGFRB, FGFR1, JAK2, ABL1, or FLT3—are now classified by the 2022 WHO classification as “myeloid/lymphoid neoplasms with eosinophilia and tyrosine-kinase fusion genes (MLN-TK)” [ 1 ] .Among these, FIP1L1::PDGFRA predominates; nine additional fusion partners of PDGFRA include BCR, ETV6, KIF5B, CDK5RAP2, STRN, TNKS2, FOXP1, AKAP9 and NRF1 [ 1 , 2 ] . CUT-like homeobox1(CUX1), a haplo-insufficient tumor suppressor on 7q, is recurrently detected in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN), conferring adverse prognosis [ 3 , 4 ] , but has not previously been reported as a fusion partner. We describe the first case of CUX1-PDGFRA in an adult male with hypereosinophilia who is about to receive imatinib treatment. Case presentation A 52-year-old Chinese male patient was referred for asymptomatic eosinophilia that had persisted for over two months. He had undergone curative-intent resection of early-stage lung cancer 2 years earlier and had received neither radiotherapy nor chemotherapy. There was no relevant family or toxic exposure history. Physical examination revealed no hepatosplenomegaly or adenopathy. Complete blood count showed hemoglobin (Hb) 143 g/L, platelet count (PLT) 143×109/L, white blood cell count (WBC) 18.73×109/L, and eosinophilia count 8.83×109/L. Troponin T and Troponin I were within the reference level. Echocardiography and electrocardiography did not show any functional impairment of the heart. Pulmonary function tests and whole-body CT imaging were unremarkable. Bone-marrow aspirate and trephine biopsy demonstrated active marrow proliferation with increased cytoplasmic granules in granulocytes and marked eosinophilia (23% of nucleated cells), while erythrocytic, lymphocytic, and megakaryocytic lineages were relatively normal. Myeloblasts and promyelocytes were not increased. Flow cytometry confirmed 32.4% eosinophils with no immunophenotypic aberrancy in myeloblasts. Conventional cytogenetics revealed t(4;7)(q12;q22) [20/20 metaphases] (Fig. 1 A). Targeted RNA sequencing identified an in-frame CUX1::PDGFRA fusion joining exon 8 of CUX1 (7q22) to exon 12 of PDGFRA (4q12), breakpoints concordant with the translocation. To further verify this previously undiscovered fusion gene, we conducted quantitative analysis targeting CUX1::PDGFRA using peripheral blood. The fusion transcript comprised 64.9% of peripheral-blood RNA (Fig. 1 B-D). Targeted next-generation sequencing detected a low-level DNMT3A variant (VAF 1.4%); JAK2, CALR and MPL were wild-type. A diagnosis of myeloid/lymphoid neoplasm with eosinophilia and PDGFRA rearrangement (MLN-TK) was made, and imatinib 100 mg daily was recommended. However, treatment was not initiated immediately due to personal reasons of the patient. He is scheduled to commence imatinib treatment soon. Discussion FIP1L1::PDGFRA generated by an 800-kb cryptic del(4q12), is the dominant lesion in MLN-TK. The fusion of FIP1L1 and PDGFRA genes disrupts the autoinhibitory juxtamembrane domain of PDGFRA, and renders the kinase constitutively active and drives clonal eosinophil expansion [ 5 ] .Other rare partner gene fusions for PDGFRA that have been detected thus far including BCR (22q11.23), ETV6 (12p13), KIF5B (10p11), CDK5RAP2 (9q33), STRN (2p24), TNKS2 (10q23), FOXP1 (3p14), AKAP9 (7q21.2) and NRF1 (7q32) [ 1 , 2 ] . We now add CUX1 as the eleventh PDGFRA fusion and the third originating from chromosome band 7q, expanding the molecular spectrum of MLN-TK. CUT-like homeobox 1 (CUX1, formerly CDP/CUTL1) maps to 7q22.1 and encodes an evolutionarily conserved homeodomain transcriptional regulator that governs development, cell migration, proliferation, differentiation and DNA-damage repair [ 6 ] . CUX1 has been characterized as a haplo-insufficient tumor suppressor gene in hematologic neoplasms: mono-allelic loss or inactivating mutations (and, rarely, chromosomal translocation) are sufficient to promote neoplastic transformation. Consequently, CUX1 loss-of-function is recurrent in myeloid malignancies including myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and is associated with poor outcome [ 3 , 4 ] . The entire deletion of chromosome 7 or its long arm [-7/del (7q)] as one of the most common chromosomal abnormalities in high-risk myeloid disease is considered an adverse prognostic event [ 7 ] . Mechanistically, CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1(phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth [ 4 ] , impairs DNA-damage repair [ 3 ] , and induces apoptotic evasion [ 8 ] , collectively sustaining myeloid neoplasms. Fusion transcripts involving CUX1 are exceptional. Only two have been documented in hematological malignancies: NUTM1::CUX1 in B-cell lymphoblastic leukemia [ 9 ] and CUX1::FGFR1 in MLN-TK [ 10 ] .We provide the first evidence that CUX1 can also recombine with PDGFRA, expanding the spectrum of kinase-activating fusions that substitute for canonical loss-of-function mechanisms. At presentation, most MLN-TK patients already show end-organ damage involving heart, lung or central nervous system; however, 10–20% are completely asymptomatic [ 11 ] . In the largest national series of FIP1L1::PDGFRA-positive cases [ 11 ] , 17% were discovered incidentally during routine blood work, underscoring the mandate to screen every patient with persistent unexplained hypereosinophilia. Break-apart FISH rapidly confirms involvement of PDGFRA, PDGFRB or FGFR1, but precise partner identification requires targeted RNA sequencing or case-specific RT-PCR. Next-generation sequencing (NGS) frequently uncovers additional genetic abnormalities in MLN-TK. In our patient, we detected a low-level DNMT3A variant (VAF 1.4%). Baer et al. profiled 61 eosinophilia-associated neoplasms bearing PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2 rearrangements and documented at least one accessory mutation in 23% of cases, most often affecting ASXL1, BCOR, DNMT3A, TET2, RUNX1, ETV6, NRAS, STAT5B or ZRSR212. The clinical significance of these sub-clonal mutations remains undefined; longitudinal studies are required to establish whether they modulate response to tyrosine-kinase inhibition or predispose to disease transformation. Imatinib is the first-line treatment for patients with PDGFRA-rearranged MLN-TK and has dramatically altered the natural history of these patients [ 5 ] . Almost all patients with a PDGFRA fusion are sensitive to imatinib and can achieve rapid and durable hematologic and molecular response. Primary and secondary resistance are unusual [ 5 ] . Although the recommended dosage is 100–400 mg daily, 100mg daily is sufficient to elicit complete molecular remission (CMR) in a majority of patients [ 5 ] . Of note, patients with PDGFRA variants other than FIP1L1::PDGFRA are also sensitive to imatinib therapy [ 13 ] . Whether patients with asymptomatic eosinophilia, just like the patient we report, should be treated immediately remains contentious. Peter et al suggest that for patients who are not suffering from organ dysfunction, especially when the eosinophil count is low, watchful waiting may be possible [ 14 ] . Thresholds of 1.5-2.0×10⁹/L have been suggested as treatment triggers with a higher risk of organ damage [ 15 ] . However, given the severe consequences of organ damage, the risk of transforming into other more severe hematologic malignancies, and the excellent efficacy of imatinib, consensus has emerged that these individuals should be treated immediately regardless of the absolute eosinophil count and symptoms. Our patient, although asymptomatic, had 8.8×10⁹/L eosinophils and was therefore advised to start on imatinib 100 mg daily without delay. In summary, we identify CUX1 as a novel 5′ partner of PDGFRA in MLN-TK. The exquisite sensitivity of PDGFRA fusions to imatinib predicts prolonged leukemia-free survival; nevertheless, the functional consequences of CUX1 disruption—specifically whether the translocation abolishes its tumor-suppressor activity and predisposes to evolution of secondary myeloid neoplasia—remain to be defined. Life-long molecular monitoring is therefore warranted. Declarations Written informed consent has been obtained from the patient to publish the details of his medical case and accompanying images. No funds, grants, or other support was received. Ethics approval The author(s) declared no competing financial interests with respect to the research, authorship, and/or publication of this article. The study was approved by the Ethics Committee of Yantai Yuhuangding Hospital, Qingdao University, Shandong, China. Author contributions All authors contributed to the analysis and interpretation of data. Jinyao Ning and Xiaoqian Liu contributed to the conception of the study and the critical revision of the manuscript. Lei Wang was responsible for drafting the manuscript. Yinghui Liu contributed to the material preparation and update of reference lists. XC was responsible for follow-up of the patient. All authors read and approved the final manuscript. References Khoury JD, Solary E, Abla O et al (2022) The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 36:1703-1719. https://doi.org/10.1038/s41375-022-01613-1 Liu J, Feng Y, Zhang Y, Xiao Y, Liu X, Xiao T, Zou J, Fan K, Lu L, Yang X, Gong J (2025) Identification of a novel NRF1::PDGFRA fusion in myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions. Front Oncol 15:1552928. https://doi.org/10.3389/fonc.2025.1552928 Aly M, Ramdzan ZM, Nagata Y et al (2019) Distinct clinical and biological implications of CUX1 in myeloid neoplasms. Blood Adv 3:2164-2178. https://doi.org/10.1182/bloodadvances.2018028423 Wong CC, Martincorena I, Rust AG et al (2014) Inactivating CUX1 mutations promote tumorigenesis. Nat Genet 46:33-38. https://doi.org/10.1038/ng.2846 Reiter A, Gotlib J (2017) Myeloid neoplasms with eosinophilia. Blood 129(6):704-714. https://doi.org/10.1182/blood-2016-10-695973 Liu N, Sun Q, Wan L, Wang X, Feng Y, Luo J, Wu H (2020) CUX1, A controversial player in tumor development. Front Oncol https://doi.org/10:738. DOI: https://doi.org/10.3389/fonc.2020.00738 Jerez A, Sugimoto Y, Makishima H et al (2012) Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis. Blood 119:6109-6117. https://doi.org/10.1182/blood-2011-12-397620 Supper E, Rudat S, Iyer V, Droop A, Wong K, Spinella J, Thomas P, Sauvageau G, Adams DJ, Wong CC (2021) Cut-like homeobox 1 (CUX1) tumor suppressor gene haploinsufficiency induces apoptosis evasion to sustain myeloid leukemia. Nat Commun 12:2482. https://doi.org/10.1038/s41467-021-22750-8 Boer JM, Valsecchi MG, Hormann FM et al (2021) Favorable outcome of NUTM1-rearranged infant and pediatric B cell precursor acute lymphoblastic leukemia in a collaborative international study. Leukemia35(10):2978-2982. https://doi.org/10.1038/s41375-021-01333-y Wasag B, Lierman E, Meeus P, Cools J, Vandenberghe P et al (2011) The kinase inhibitor TKI258 is active against the novel CUX1-FGFR1 fusion detected in a patient with T-lymphoblastic leukemia/lymphoma and t(7;8)(q22;p11).Haematologica 96:922-926. https://doi.org/10.3324/haematol.2010.036558 Rohmer J, Couteau-Chardon A, Trichereau J et al (2020) Epidemiology, clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients. Am J Hematol 95:1314-1323. https://doi.org/10.1002/ajh.25945 Baer C, Muehlbacher V, Kern W, Haferlach C, Haferlach T (2018) Molecular genetic characterization of myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2. Haematol-Hematol J 103:e348-350. https://doi.org/10.3324/haematol.2017.187302 Pozdnyakova O, Orazi A, Kelemen K, King R, Reichard KK, Craig FE, Quintanilla-Martinez L, Rimsza L, George TI, Horny HP, Wang SA (2021) Myeloid/lymphoid neoplasms associated with eosinophilia and rearrangements of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2. Am J Clin Pathol 155:160-178. https://doi.org/10.1093/ajcp/aqaa208 Valent P (2009) Pathogenesis, classification, and therapy of eosinophilia and eosinophil disorders. Blood 23:157-165. https://doi.org/10.1016/j.blre.2009.01.001 Shomali W, Gotlib J (2024) World Health Organization and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management.Am J Hematol 99:946-968. https://doi.org/10.1002/ajh.27287 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8357179","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":572617361,"identity":"c88ffad6-bfa3-416c-90a0-3fd78193ca1e","order_by":0,"name":"Lei Wang","email":"","orcid":"","institution":"Yuhuangding Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Wang","suffix":""},{"id":572617362,"identity":"73117203-bf9b-4d55-bb0f-e7d4134fb6a5","order_by":1,"name":"Yinghui Liu","email":"","orcid":"","institution":"Yuhuangding Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yinghui","middleName":"","lastName":"Liu","suffix":""},{"id":572617363,"identity":"e11777a2-c26e-448c-9801-8356256948db","order_by":2,"name":"Xiaoxia Chu","email":"","orcid":"","institution":"Yuhuangding Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaoxia","middleName":"","lastName":"Chu","suffix":""},{"id":572617364,"identity":"e306fbcb-4626-4586-a7eb-85528f2afc01","order_by":3,"name":"Jinyao Ning","email":"","orcid":"","institution":"Yuhuangding Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jinyao","middleName":"","lastName":"Ning","suffix":""},{"id":572617365,"identity":"256b228b-2c7e-492d-99a8-35e26ad24b96","order_by":4,"name":"Xiaoqian Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIie3PPQrCMBTA8ZRAurR2fUH0DCkP/AAP0yxORRCXDqIFoaNeQPQKTp2FgpPujq2uHZzEScyiSIfG0SF/SHiB/CAhxGT6wxpUbYFajBCruEXQ9nSEfRGKcOwhj3XkewY3ieROS2ynA/l00Frap0zwDVg7QovLufZhDorgMMTEGcl8nALtEoYY1hM/D1gmExKi4CmwfuywpoaIffBUxCs74K5BHfXEz2WiCISKxAA/EDYRcqn+AiUiHEDwheYvnpel/HEftLar0C9u09l8ZS+Kax15Z8Wfkf5wvUJMJpPJVOkFKjdAiY1YfpkAAAAASUVORK5CYII=","orcid":"","institution":"Yuhuangding Hospital","correspondingAuthor":true,"prefix":"","firstName":"Xiaoqian","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2025-12-14 09:53:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8357179/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8357179/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":100131998,"identity":"a3e16fcd-f3d9-47d2-a22b-8170cc97b2cf","added_by":"auto","created_at":"2026-01-13 10:21:54","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":301341,"visible":true,"origin":"","legend":"","description":"","filename":"CUX1PDGFRAAnnalsofHematology.docx","url":"https://assets-eu.researchsquare.com/files/rs-8357179/v1/068230ea6472a33ac5e345b9.docx"},{"id":100131991,"identity":"7d334b69-5cfa-4e3f-acef-f8104682045a","added_by":"auto","created_at":"2026-01-13 10:21:54","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6149,"visible":true,"origin":"","legend":"","description":"","filename":"e562c1f38c204bf49b7ef85ba0045b9c.json","url":"https://assets-eu.researchsquare.com/files/rs-8357179/v1/ad7babe80a6105a6f72d5a96.json"},{"id":100367797,"identity":"caba5608-8f09-4c88-a55a-12553d86d374","added_by":"auto","created_at":"2026-01-16 07:57:17","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":44308,"visible":true,"origin":"","legend":"","description":"","filename":"e562c1f38c204bf49b7ef85ba0045b9c1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8357179/v1/5f2a62232d9880b2b64c5d65.xml"},{"id":100366768,"identity":"47929e92-a081-472c-8ecb-f6d4fc3420e1","added_by":"auto","created_at":"2026-01-16 07:56:31","extension":"jpeg","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":450422,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8357179/v1/a0482ea14e1342b6dc4ec9f8.jpeg"},{"id":100131993,"identity":"df0aae30-51ba-446d-9131-82772a9ebd28","added_by":"auto","created_at":"2026-01-13 10:21:54","extension":"jpeg","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":363931,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8357179/v1/24ca8f2d566a532e272f966c.jpeg"},{"id":100379836,"identity":"9bde0f13-f59e-478c-aeb6-fd0556965639","added_by":"auto","created_at":"2026-01-16 09:42:35","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":97219,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8357179/v1/a530f1906bd98c64a6f1a276.png"},{"id":100366949,"identity":"a9ee2f9d-9262-44f8-9c28-75310c831852","added_by":"auto","created_at":"2026-01-16 07:56:41","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":86400,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8357179/v1/8058d557a8bee3a15884074b.png"},{"id":100366273,"identity":"3335d3a2-1a96-4c82-9da0-66113101981d","added_by":"auto","created_at":"2026-01-16 07:56:10","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":43225,"visible":true,"origin":"","legend":"","description":"","filename":"e562c1f38c204bf49b7ef85ba0045b9c1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8357179/v1/dde20371ec2f7fa695603587.xml"},{"id":100367259,"identity":"0f554fa5-15bb-43f9-b5b3-b0abc4189613","added_by":"auto","created_at":"2026-01-16 07:56:53","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":49797,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8357179/v1/254a7a8202141235f0f939ff.html"},{"id":100366499,"identity":"43531daf-d60c-44e0-a941-436a0ffecb5e","added_by":"auto","created_at":"2026-01-16 07:56:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":278484,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Karyotype showing abnormal chromosomes identified by R-banding. (B)Schematic representation of the recombination between the CUX1 and PDGFRA genes. (C) Identification of a novel CUX1::PDGFRA fusion gene by RNA sequencing. (D) The domain of the CUX1-PDGFRA fusion protein.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8357179/v1/cc7b93f943678b3df7f82d0e.png"},{"id":102694968,"identity":"08d5c2ac-c172-4b6b-984d-e41d959c9dcd","added_by":"auto","created_at":"2026-02-15 07:39:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":541771,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8357179/v1/a1f6a1d9-ef04-4c41-aa44-83f4e54d5037.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"CUX1–PDGFRA: a novel fusion in myeloid/lymphoid neoplasms with eosinophilia","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePDGFRB, FGFR1, JAK2, ABL1, or FLT3\u0026mdash;are now classified by the 2022 WHO classification as \u0026ldquo;myeloid/lymphoid neoplasms with eosinophilia and tyrosine-kinase fusion genes (MLN-TK)\u0026rdquo; \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e.Among these, FIP1L1::PDGFRA predominates; nine additional fusion partners of PDGFRA include BCR, ETV6, KIF5B, CDK5RAP2, STRN, TNKS2, FOXP1, AKAP9 and NRF1\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. CUT-like homeobox1(CUX1), a haplo-insufficient tumor suppressor on 7q, is recurrently detected in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN), conferring adverse prognosis\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e, but has not previously been reported as a fusion partner. We describe the first case of CUX1-PDGFRA in an adult male with hypereosinophilia who is about to receive imatinib treatment.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 52-year-old Chinese male patient was referred for asymptomatic eosinophilia that had persisted for over two months. He had undergone curative-intent resection of early-stage lung cancer 2 years earlier and had received neither radiotherapy nor chemotherapy. There was no relevant family or toxic exposure history. Physical examination revealed no hepatosplenomegaly or adenopathy. Complete blood count showed hemoglobin (Hb) 143 g/L, platelet count (PLT) 143\u0026times;109/L, white blood cell count (WBC) 18.73\u0026times;109/L, and eosinophilia count 8.83\u0026times;109/L. Troponin T and Troponin I were within the reference level. Echocardiography and electrocardiography did not show any functional impairment of the heart. Pulmonary function tests and whole-body CT imaging were unremarkable. Bone-marrow aspirate and trephine biopsy demonstrated active marrow proliferation with increased cytoplasmic granules in granulocytes and marked eosinophilia (23% of nucleated cells), while erythrocytic, lymphocytic, and megakaryocytic lineages were relatively normal. Myeloblasts and promyelocytes were not increased. Flow cytometry confirmed 32.4% eosinophils with no immunophenotypic aberrancy in myeloblasts. Conventional cytogenetics revealed t(4;7)(q12;q22) [20/20 metaphases] (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Targeted RNA sequencing identified an in-frame CUX1::PDGFRA fusion joining exon 8 of CUX1 (7q22) to exon 12 of PDGFRA (4q12), breakpoints concordant with the translocation. To further verify this previously undiscovered fusion gene, we conducted quantitative analysis targeting CUX1::PDGFRA using peripheral blood. The fusion transcript comprised 64.9% of peripheral-blood RNA (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003eB-D). Targeted next-generation sequencing detected a low-level DNMT3A variant (VAF 1.4%); JAK2, CALR and MPL were wild-type. A diagnosis of myeloid/lymphoid neoplasm with eosinophilia and PDGFRA rearrangement (MLN-TK) was made, and imatinib 100 mg daily was recommended. However, treatment was not initiated immediately due to personal reasons of the patient. He is scheduled to commence imatinib treatment soon.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eFIP1L1::PDGFRA generated by an 800-kb cryptic del(4q12), is the dominant lesion in MLN-TK. The fusion of FIP1L1 and PDGFRA genes disrupts the autoinhibitory juxtamembrane domain of PDGFRA, and renders the kinase constitutively active and drives clonal eosinophil expansion\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.Other rare partner gene fusions for PDGFRA that have been detected thus far including BCR (22q11.23), ETV6 (12p13), KIF5B (10p11), CDK5RAP2 (9q33), STRN (2p24), TNKS2 (10q23), FOXP1 (3p14), AKAP9 (7q21.2) and NRF1 (7q32)\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. We now add CUX1 as the eleventh PDGFRA fusion and the third originating from chromosome band 7q, expanding the molecular spectrum of MLN-TK.\u003c/p\u003e \u003cp\u003eCUT-like homeobox 1 (CUX1, formerly CDP/CUTL1) maps to 7q22.1 and encodes an evolutionarily conserved homeodomain transcriptional regulator that governs development, cell migration, proliferation, differentiation and DNA-damage repair\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. CUX1 has been characterized as a haplo-insufficient tumor suppressor gene in hematologic neoplasms: mono-allelic loss or inactivating mutations (and, rarely, chromosomal translocation) are sufficient to promote neoplastic transformation. Consequently, CUX1 loss-of-function is recurrent in myeloid malignancies including myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and is associated with poor outcome\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. The entire deletion of chromosome 7 or its long arm [-7/del (7q)] as one of the most common chromosomal abnormalities in high-risk myeloid disease is considered an adverse prognostic event\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Mechanistically, CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1(phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e, impairs DNA-damage repair\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e, and induces apoptotic evasion\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, collectively sustaining myeloid neoplasms. Fusion transcripts involving CUX1 are exceptional. Only two have been documented in hematological malignancies: NUTM1::CUX1 in B-cell lymphoblastic leukemia\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e and CUX1::FGFR1 in MLN-TK\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e.We provide the first evidence that CUX1 can also recombine with PDGFRA, expanding the spectrum of kinase-activating fusions that substitute for canonical loss-of-function mechanisms.\u003c/p\u003e \u003cp\u003eAt presentation, most MLN-TK patients already show end-organ damage involving heart, lung or central nervous system; however, 10\u0026ndash;20% are completely asymptomatic\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. In the largest national series of FIP1L1::PDGFRA-positive cases\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e, 17% were discovered incidentally during routine blood work, underscoring the mandate to screen every patient with persistent unexplained hypereosinophilia. Break-apart FISH rapidly confirms involvement of PDGFRA, PDGFRB or FGFR1, but precise partner identification requires targeted RNA sequencing or case-specific RT-PCR.\u003c/p\u003e \u003cp\u003eNext-generation sequencing (NGS) frequently uncovers additional genetic abnormalities in MLN-TK. In our patient, we detected a low-level DNMT3A variant (VAF 1.4%). Baer et al. profiled 61 eosinophilia-associated neoplasms bearing PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2 rearrangements and documented at least one accessory mutation in 23% of cases, most often affecting ASXL1, BCOR, DNMT3A, TET2, RUNX1, ETV6, NRAS, STAT5B or ZRSR212. The clinical significance of these sub-clonal mutations remains undefined; longitudinal studies are required to establish whether they modulate response to tyrosine-kinase inhibition or predispose to disease transformation.\u003c/p\u003e \u003cp\u003eImatinib is the first-line treatment for patients with PDGFRA-rearranged MLN-TK and has dramatically altered the natural history of these patients\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Almost all patients with a PDGFRA fusion are sensitive to imatinib and can achieve rapid and durable hematologic and molecular response. Primary and secondary resistance are unusual\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Although the recommended dosage is 100\u0026ndash;400 mg daily, 100mg daily is sufficient to elicit complete molecular remission (CMR) in a majority of patients\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Of note, patients with PDGFRA variants other than FIP1L1::PDGFRA are also sensitive to imatinib therapy\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Whether patients with asymptomatic eosinophilia, just like the patient we report, should be treated immediately remains contentious. Peter et al suggest that for patients who are not suffering from organ dysfunction, especially when the eosinophil count is low, watchful waiting may be possible\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Thresholds of 1.5-2.0\u0026times;10⁹/L have been suggested as treatment triggers with a higher risk of organ damage\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. However, given the severe consequences of organ damage, the risk of transforming into other more severe hematologic malignancies, and the excellent efficacy of imatinib, consensus has emerged that these individuals should be treated immediately regardless of the absolute eosinophil count and symptoms. Our patient, although asymptomatic, had 8.8\u0026times;10⁹/L eosinophils and was therefore advised to start on imatinib 100 mg daily without delay.\u003c/p\u003e \u003cp\u003eIn summary, we identify CUX1 as a novel 5\u0026prime; partner of PDGFRA in MLN-TK. The exquisite sensitivity of PDGFRA fusions to imatinib predicts prolonged leukemia-free survival; nevertheless, the functional consequences of CUX1 disruption\u0026mdash;specifically whether the translocation abolishes its tumor-suppressor activity and predisposes to evolution of secondary myeloid neoplasia\u0026mdash;remain to be defined. Life-long molecular monitoring is therefore warranted.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eWritten informed consent has been obtained from the patient to publish the details of his medical case and accompanying images. No funds, grants, or other support was received.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) declared no competing financial interests with respect to the research, authorship, and/or publication of this article. The study was approved by the Ethics Committee of Yantai Yuhuangding Hospital, Qingdao University, Shandong, China.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the analysis and interpretation of data. Jinyao Ning and Xiaoqian Liu contributed to the conception of the study and the critical revision of the manuscript. Lei Wang was responsible for drafting the manuscript. Yinghui Liu contributed to the material preparation and update of reference lists. XC was responsible for follow-up of the patient. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKhoury JD, Solary E, Abla O et al (2022) The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 36:1703-1719. https://doi.org/10.1038/s41375-022-01613-1\u003c/li\u003e\n\u003cli\u003eLiu J, Feng Y, Zhang Y, Xiao Y, Liu X, Xiao T, Zou J, Fan K, Lu L, Yang X, Gong J (2025) Identification of a novel NRF1::PDGFRA fusion in myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions. Front Oncol 15:1552928. https://doi.org/10.3389/fonc.2025.1552928\u003c/li\u003e\n\u003cli\u003eAly M, Ramdzan ZM, Nagata Y et al (2019) Distinct clinical and biological implications of CUX1 in myeloid neoplasms. Blood Adv 3:2164-2178. https://doi.org/10.1182/bloodadvances.2018028423\u003c/li\u003e\n\u003cli\u003eWong CC, Martincorena I, Rust AG et al (2014) Inactivating CUX1 mutations promote tumorigenesis. Nat Genet 46:33-38. https://doi.org/10.1038/ng.2846\u003c/li\u003e\n\u003cli\u003eReiter A, Gotlib J (2017) Myeloid neoplasms with eosinophilia. Blood 129(6):704-714. https://doi.org/10.1182/blood-2016-10-695973\u003c/li\u003e\n\u003cli\u003eLiu N, Sun Q, Wan L, Wang X, Feng Y, Luo J, Wu H (2020) CUX1, A controversial player in tumor development. Front Oncol https://doi.org/10:738. DOI: https://doi.org/10.3389/fonc.2020.00738\u003c/li\u003e\n\u003cli\u003eJerez A, Sugimoto Y, Makishima H et al (2012) Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis. Blood 119:6109-6117. https://doi.org/10.1182/blood-2011-12-397620\u003c/li\u003e\n\u003cli\u003eSupper E, Rudat S, Iyer V, Droop A, Wong K, Spinella J, Thomas P, Sauvageau G, Adams DJ, Wong CC (2021) Cut-like homeobox 1 (CUX1) tumor suppressor gene haploinsufficiency induces apoptosis evasion to sustain myeloid leukemia. Nat Commun 12:2482. https://doi.org/10.1038/s41467-021-22750-8\u003c/li\u003e\n\u003cli\u003eBoer JM, Valsecchi MG, Hormann FM et al (2021) Favorable outcome of NUTM1-rearranged infant and pediatric B cell precursor acute lymphoblastic leukemia in a collaborative international study. Leukemia35(10):2978-2982. https://doi.org/10.1038/s41375-021-01333-y\u003c/li\u003e\n\u003cli\u003eWasag B, Lierman E, Meeus P, Cools J, Vandenberghe P et al (2011) The kinase inhibitor TKI258 is active against the novel CUX1-FGFR1 fusion detected in a patient with T-lymphoblastic leukemia/lymphoma and t(7;8)(q22;p11).Haematologica 96:922-926. https://doi.org/10.3324/haematol.2010.036558\u003c/li\u003e\n\u003cli\u003eRohmer J, Couteau-Chardon A, Trichereau J et al (2020) Epidemiology, clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients. Am J Hematol 95:1314-1323. https://doi.org/10.1002/ajh.25945\u003c/li\u003e\n\u003cli\u003eBaer C, Muehlbacher V, Kern W, Haferlach C, Haferlach T (2018) Molecular genetic characterization of myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2. Haematol-Hematol J 103:e348-350. https://doi.org/10.3324/haematol.2017.187302\u003c/li\u003e\n\u003cli\u003ePozdnyakova O, Orazi A, Kelemen K, King R, Reichard KK, Craig FE, Quintanilla-Martinez L, Rimsza L, George TI, Horny HP, Wang SA (2021) Myeloid/lymphoid neoplasms associated with eosinophilia and rearrangements of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2. Am J Clin Pathol 155:160-178. https://doi.org/10.1093/ajcp/aqaa208\u003c/li\u003e\n\u003cli\u003eValent P (2009) Pathogenesis, classification, and therapy of eosinophilia and eosinophil disorders. Blood 23:157-165. https://doi.org/10.1016/j.blre.2009.01.001\u003c/li\u003e\n\u003cli\u003eShomali W, Gotlib J (2024) World Health Organization and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management.Am J Hematol 99:946-968. https://doi.org/10.1002/ajh.27287\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"eosinophilia, myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions, PDGFRA, CUX1, CUX1::PDGFRA, imatinib","lastPublishedDoi":"10.21203/rs.3.rs-8357179/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8357179/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEosinophilic disorders are a heterogeneous group of neoplastic and non-neoplastic conditions, characterized by increased number of eosinophils in the peripheral blood and sometimes lead to eosinophil-driven organ damage and dysfunction. Myeloid/lymphoid neoplasms with eosinophilia and tyrosine-kinase fusion genes (MLN-TK) is a group of hematologic neoplasms resulting from the formation of abnormal fusion genes that encode constitutively activated tyrosine kinases. The FIP1L1-PDGFRA fusion gene is the most common genetic abnormality detected in MLN-TK and nine rarer PDGFRA partners have also been documented at the time of writing. A novel fusion gene CUX1-PDGFRA was identified in an adult male with myeloid/lymphoid neoplasms with eosinophilia and tyrosine-kinase fusion genes (MLN-TK) through targeted RNA sequencing. This is the eleventh partner gene fusions for PDGFRA in MLN-TK discovered so far. Given the exquisite responsiveness of PDGFRA fusions to imatinib, we recommended imatinib at a dose of 100mg daily to the patient. The therapeutic response and prognosis remains to be further observed.\u003c/p\u003e","manuscriptTitle":"CUX1–PDGFRA: a novel fusion in myeloid/lymphoid neoplasms with eosinophilia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-13 10:21:49","doi":"10.21203/rs.3.rs-8357179/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9d958bb4-688e-4adc-acba-beddb3ada764","owner":[],"postedDate":"January 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-15T07:39:12+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-13 10:21:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8357179","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8357179","identity":"rs-8357179","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}