Spontaneous Remission and Clonal Relapse in Congenital Infant Leukemia: Single-Cell Atlas Profiling and Curative Transplantation

Spontaneous Remission and Clonal Relapse in Congenital Infant Leukemia: Single-Cell Atlas Profiling and Curative Transplantation | 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 comment Spontaneous Remission and Clonal Relapse in Congenital Infant Leukemia: Single-Cell Atlas Profiling and Curative Transplantation Chaoban Wang, Shijing Ge, Gao Ju, Rong Yang, xia guo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7714797/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 Congenital leukemia is an exceptionally rare malignancy with an incidence below five per million births and poor prognosis, especially in cases with KMT2A rearrangements. Spontaneous remission (SR) is an uncommon phenomenon; since 1996, only five SR cases with KMT2A rearrangements have been reported worldwide. We describe a neonate with congenital AML-M5 carrying a KMT2A-MLLT3 fusion, who achieved SR without chemotherapy but relapsed at 5 months with extensive extramedullary disease. At relapse, we performed the world’s first single-cell transcriptomic sequencing of SR-associated congenital leukemia. Analysis showed no proliferative advantage in leukemic progenitors but marked autophagy upregulation and an incomplete immune evasion phenotype, suggesting transient dormancy and partial susceptibility to cytotoxic T-cell surveillance. The patient subsequently achieved molecular remission with CCLG-AML-2024 chemotherapy and remained disease-free following matched unrelated HSCT at 12 months. This case highlights the fragile balance between leukemic clones and host immunity in early life, suggesting autophagy activation and immune sensitivity as natural restraints on leukemogenesis. It emphasizes that SR represents a temporary pause rather than cure, requiring close molecular monitoring, and provides the first single-cell atlas of SR-type congenital leukemia, offering new directions for immunomodulatory and autophagy-targeted therapies in high-risk KMT2A-rearranged leukemia. Figures Figure 1 Figure 2 Figure 3 Background Congenital leukemia is an extremely rare and life-threatening hematologic malignancy, typically diagnosed within the first four weeks of life. Owing to the scarcity of epidemiological data, its estimated incidence is approximately three per million births. (1) In congenital acute myeloid leukemia (AML), about two-thirds of patients present with cutaneous infiltration, which can occasionally occur in the absence of overt involvement of peripheral blood or bone marrow.(2, 3) The overall prognosis of congenital leukemia is generally dismal, particularly among patients harboring KMT2A rearrangements. Spontaneous remission (SR) represents a rare phenomenon in congenital infant leukemia, defined as the disappearance of leukemic manifestations and achievement of clinical or even hematologic remission without the administration of anti-leukemic therapy. In 2018, Irene Roberts and colleagues summarized the genetic features of congenital infant AML with SR, identifying KAT6A rearrangements as the predominant subtype. By contrast, cases associated with KMT2A rearrangements have been exceedingly rare, with only five reported worldwide since the first description in 1996, and very few additional cases thereafter.(1, 3–7) Although sporadic cases of congenital leukemia with SR have been reported globally and have drawn increasing attention, their extreme rarity, the unpredictable course of remission, and frequent interruption by clinical interventions (e.g., rescue therapy) render systematic investigation difficult. As a result, compared with common forms of leukemia, SR-associated congenital leukemia lacks comprehensive molecular evidence. Clinically, such cases generally follow one of two divergent trajectories: sustained long-term remission or disease relapse. Notably, when relapse occurs, the brief interval before initiation of therapy provides a unique opportunity to obtain bone marrow tumor samples that represent the only available patient-derived, treatment-naïve material (unless the disease remains refractory despite therapy). In this report, we describe a case of congenital acute monocytic leukemia with spontaneous remission in the neonatal period, followed by relapse. At relapse, we collected bone marrow samples and performed single-cell sequencing, generating the world’s first single-cell dataset of congenital leukemia with SR. Following standard chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), the patient ultimately achieved complete remission and recovery. This case not only offers unique insights into the clonal evolution and mechanisms underlying SR in congenital leukemia but also supports the curative potential of HSCT in rare neonatal leukemia phenotypes, carrying important implications for future diagnostic and therapeutic strategies. Case Presentation Postnatal Course and Spontaneous Remission We report a term female neonate, currently 15 months of age. At birth, her Apgar scores were 5–10–10. She was admitted to the NICU due to respiratory distress and diffuse “blueberry muffin–like” skin lesions (Fig. 1A). Complete blood count revealed WBC 108.65 × 10^9/L, ANC 24.88 × 10^9/L, blasts 85%, hemoglobin 166 g/L, and platelets 62 × 10^9/L. Bone marrow smears showed an inverted myeloid-to-erythroid ratio with 3.0% monoblasts (Fig. 1B). Peripheral blood testing for leukemia fusion genes identified a KMT2A-MLLT3 fusion, while immunophenotyping of peripheral blood leukemic cells revealed no abnormal antigen expression (Fig. 1C). No hepatosplenomegaly was detected, but abdominal CT indicated congenital absence of the spleen (Fig. 1D). During her NICU stay, she received respiratory support, anti-infective therapy, and symptomatic care, but no chemotherapy or corticosteroids. Remarkably, the cutaneous purpura and petechiae resolved, and her peripheral blood counts spontaneously normalized within two weeks. At 1 month of age, outpatient follow-up still detected the KMT2A-MLLT3 fusion gene in peripheral blood, but by 3 months, the fusion transcript had become undetectable. Relapse, Diagnosis, and Single-Cell Sequencing Analysis Two months after spontaneous remission, between 5 and 7 months of age, the patient developed recurrent rash over the lower abdomen that gradually spread across the body, accompanied by subcutaneous nodules. She also presented with a pink protrusion beneath the conjunctiva of the left eye, progressive bilateral scleral injection, and swelling of the periorbital and temporal soft tissues. She was readmitted to the Department of Pediatric Hematology. Bone marrow smears revealed acute monocytic leukemia (AML-M5). Immunophenotyping showed that abnormal monocytes accounted for ~ 19% of nucleated cells. Karyotype analysis demonstrated 47,XX,+?9,t(9;11)(p21;q23),del(13)(q12q22)[16]/46,XX[4]. Whole-transcriptome sequencing confirmed the KMT2A-MLLT3 fusion and identified an NRAS mutation (Fig. 2A–D). The patient also exhibited extensive extramedullary involvement. Cranial CT showed multiple patchy hyperdense lesions in the right parietal, temporal, and occipital regions, as well as the left occipital-parietal region; multiple soft tissue masses and nodules in the skull base, orbits, paranasal sinuses, and frontotemporal areas; reduced bone density and evidence of osteolytic destruction in corresponding regions (Fig. 2E–F). Chest and abdominal CT revealed a lobulated soft tissue mass anterior to the upper left iliopsoas; multiple nodules on the anterior bladder wall; markedly enlarged and irregular uterus; gastric wall thickening; and enlarged, heterogeneous kidneys—findings highly suggestive of leukemic infiltration (Fig. 2G–H). Bone marrow aspirates were collected prior to chemotherapy for single-cell RNA sequencing. CNV-based sub-clustering identified leukemic progenitors (Fig. 3A–B). Cell-cycle scoring indicated that leukemic progenitors lacked a clear proliferative advantage compared with normal progenitors (Fig. 3C–D). Notably, leukemic progenitors showed upregulation of the autophagy pathway (Fig. 3E), potentially contributing to their capacity for spontaneous remission. Furthermore, cell–cell communication analysis revealed a dual immune phenotype: on one hand, leukemic progenitors suppressed multiple immune cell functions; on the other, they remained more susceptible to cytotoxic T-cell recognition. This suggests that such leukemic progenitors may exhibit incomplete immune evasion (Fig. 3F–H). Treatment and Follow-up Following confirmation of relapse, the patient began treatment at 7 months of age with induction chemotherapy according to the CCLG-AML-2024 protocol. The first induction course consisted of venetoclax, cytarabine, homoharringtonine, and intrathecal methotrexate, cytarabine, and dexamethasone. At the end of this course (age 8 months), bone marrow smears demonstrated complete remission (CR) of AML-M5. Molecular studies showed clearance of the NRAS mutation, while KMT2A-MLLT3 transcript levels decreased to 0.04%. MRI of the head, orbits, and abdomen revealed marked resolution of previous soft tissue and lymph node lesions, with significant improvement in the uterus and kidneys and disappearance of bladder wall nodules. At 8 months of age, the patient proceeded to the second induction course with venetoclax and decitabine, plus intrathecal triple therapy. After completion (age 9 months), bone marrow examination again confirmed CR, with both KMT2A-MLLT3 fusion and single nucleotide variant (SNV) testing negative. Minimal residual disease (MRD) by flow cytometry showed no detectable abnormal cells (< 10⁻⁴). At 9 months of age, the patient entered the third course, consisting of liposomal mitoxantrone and cytarabine, plus intrathecal triple therapy. During this phase, she experienced severe chemotherapy-induced myelosuppression complicated by multiple soft tissue infections, perianal infection, and intracranial hemorrhage, which resolved with intensive anti-infective and supportive management. Post-treatment bone marrow examination at 11 months confirmed continued CR, with KMT2A-MLLT3 and NRAS negativity and MRD below detectable levels. A whole-body PET/CT scan showed no abnormal FDG uptake, with no evidence of residual leukemic infiltration in the eyes or elsewhere. At 11 months of age, the patient was admitted for allogeneic hematopoietic stem cell transplantation (HSCT) from a fully HLA-matched unrelated donor (10/10). Following pre-transplant conditioning, HSCT was performed at 12 months of age. By 13 months (June 12, 2025), bone marrow examination confirmed sustained CR, with MRD undetectable and both KMT2A-MLLT3 and NRAS negative. Discussion Congenital leukemia with SR represents one of the most unusual and poorly understood conditions in pediatric hematology. SR has been most frequently reported in congenital acute myeloid leukemia (AML) cases harboring KAT6A rearrangements. By contrast, congenital AML associated with KMT2A rearrangements generally carries a dismal prognosis, and cases with SR are exceedingly rare. Since the first report in 1996, only a handful of KMT2A-rearranged congenital leukemias with SR have been described worldwide. Our case therefore adds valuable evidence to this sparse literature and, importantly, provides the world’s first single-cell sequencing dataset in this unique setting. The rarity of SR in KMT2A-rearranged congenital leukemia raises important biological questions. In our case, the patient experienced hematologic remission within two weeks of birth without chemotherapy or corticosteroids, followed by relapse at five months of age. Single-cell RNA sequencing of bone marrow at relapse offered a unique opportunity to investigate treatment-naïve leukemic progenitors. CNV-based subclustering identified distinct leukemic populations, and cell-cycle scoring revealed that leukemic progenitors lacked a clear proliferative advantage compared with their normal counterparts. This finding suggests that these malignant cells may harbor intrinsic proliferative defects, rendering them more vulnerable to spontaneous clearance. Furthermore, leukemic progenitors demonstrated upregulation of autophagy pathways, a feature that may contribute to their instability and capacity for self-limiting disease. Autophagy has been increasingly recognized as a double-edged process in cancer biology, promoting either cell survival or cell death depending on the context.(8, 9) In our patient, the enrichment of autophagy signaling may have facilitated partial elimination of leukemic cells in the neonatal period, thereby contributing to SR. In addition, our analysis of cell–cell communication revealed a dual immune phenotype: leukemic progenitors suppressed multiple immune functions but remained relatively susceptible to cytotoxic T-cell recognition. This incomplete immune evasion further supports the notion that SR may result from a transient balance between vulnerable leukemic clones and an activated neonatal immune system.(10, 11) Collectively, these findings provide novel mechanistic insights into how SR may occur in congenital leukemia. From a clinical perspective, this case highlights several important lessons. First, SR does not equate to cure. Although the patient achieved rapid remission after birth, relapse occurred within months, underscoring the high recurrence risk associated with congenital leukemia, particularly those harboring KMT2A rearrangements.(12, 13) Thus, long-term molecular monitoring remains essential even in cases that appear to resolve spontaneously.(14) Second, the temporary remission window offered a rare opportunity to obtain treatment-naive leukemic samples for research. Because most congenital leukemia patients receive urgent rescue therapy at diagnosis, such samples are rarely available. The molecular insights generated from this case may therefore inform future studies into the biology of SR and potential therapeutic strategies. Finally, this case reinforces the role of hematopoietic stem cell transplantation (HSCT) in the management of high-risk neonatal AML. Following relapse, our patient responded to induction chemotherapy and ultimately underwent successful allogeneic HSCT, achieving sustained complete remission. This outcome supports previous reports suggesting that HSCT can be curative in rare neonatal leukemia phenotypes, despite their otherwise poor prognosis.(15) It also extends the evidence base for HSCT applicability to cases with prior SR and relapse, a scenario not frequently documented in the literature. Conclusion Our report provides several perspectives for clinical practice: congenital leukemia carries a high risk of relapse even after spontaneous remission, warranting long-term molecular monitoring. More importantly, as the first single-cell sequencing analysis of such a patient worldwide, our findings suggest that leukemic cells in this condition may harbor intrinsic defects, offering new insights into the mechanisms of spontaneous remission. In addition, the successful cure of this rare AML subtype through HSCT further supports the applicability of HSCT in this special setting. Declarations Funding: Not applicable. Conflicts of interest: The authors have no conflicts of interest to declare. Author contributions: Chaoban Wang, Rong Yang : Conception and design, Collection and assembly of data, Data analysis and interpretation; Shijing Ge, Gao Ju, Guo Xia：Conception and design, administrative support. All authors: Manuscript writing and final approval of the manuscript. Data availability The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Ethics approval and consent to participate This study was approved by the Ethics Committee of West China Second Hospital of Sichuan University and followed the Declaration of Helsinki principles (Approval No. 2021YFS0028). Written informed consent was obtained from the minor(s)’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article. Consent for publication Written consent for publication was obtained from all the participants involved in our study. References Roberts I, Fordham NJ, Rao A, Bain BJ. Neonatal leukaemia. Br J Haematol. 2018;182(2):170-84. Epub 20180528. doi: 10.1111/bjh.15246. PubMed PMID: 29806701. Zhang IH, Zane LT, Braun BS, Maize J, Jr., Zoger S, Loh ML. Congenital leukemia cutis with subsequent development of leukemia. J Am Acad Dermatol. 2006;54(2 Suppl):S22-7. doi: 10.1016/j.jaad.2005.04.038. PubMed PMID: 16427986. Lee EG, Kim TH, Yoon MS, Lee HJ. Congenital leukemia cutis preceding acute myeloid leukemia with t(9;11)(p22;q23), MLL-MLLT3. J Dermatol. 2013;40(7):570-1. Epub 20130417. doi: 10.1111/1346-8138.12164. PubMed PMID: 23594338. Monpoux F, Lacour JP, Hatchuel Y, Hofman P, Raynaud S, Sudaka I, et al. Congenital leukemia cutis preceding monoblastic leukemia by 3 months. Pediatr Dermatol. 1996;13(6):472-6. doi: 10.1111/j.1525-1470.1996.tb00727.x. PubMed PMID: 8987056. Bacchetta J, Douvillez B, Warin L, Girard S, Pagès MP, Rebaud P, et al. [Blueberry Muffin Baby and spontaneous remission of neonatal leukaemia]. Arch Pediatr. 2008;15(8):1315-9. Epub 20080701. doi: 10.1016/j.arcped.2008.04.030. PubMed PMID: 18595669. Jesudas R, Buck SA, Savasan S. Spontaneous remission of congenital AML with skin involvement and t(1;11)(p32;q23). Pediatr Blood Cancer. 2017;64(3). Epub 20160929. doi: 10.1002/pbc.26269. PubMed PMID: 27682159. Gyárfás T, Wintgens J, Biskup W, Oschlies I, Klapper W, Siebert R, et al. Transient spontaneous remission in congenital MLL-AF10 rearranged acute myeloid leukemia presenting with cardiorespiratory failure and meconium ileus. Mol Cell Pediatr. 2016;3(1):30. Epub 20160829. doi: 10.1186/s40348-016-0061-7. PubMed PMID: 27510896; PubMed Central PMCID: PMC5002396. Niu X, You Q, Hou K, Tian Y, Wei P, Zhu Y, et al. Autophagy in cancer development, immune evasion, and drug resistance. Drug Resist Updat. 2025;78:101170. Epub 20241115. doi: 10.1016/j.drup.2024.101170. PubMed PMID: 39603146. Haghi A, Mohammadi Kian M, Salemi M, Eghdami MR, Nikbakht M. The Question of Survival or Death: What Is the Role of Autophagy in Acute Myeloid Leukemia (AML)? Int J Hematol Oncol Stem Cell Res. 2022;16(4):250-63. doi: 10.18502/ijhoscr.v16i4.10883. PubMed PMID: 36883106; PubMed Central PMCID: PMC9985813. Chen Y, Gibson SB. Three dimensions of autophagy in regulating tumor growth: cell survival/death, cell proliferation, and tumor dormancy. Biochim Biophys Acta Mol Basis Dis. 2021;1867(12):166265. Epub 20210904. doi: 10.1016/j.bbadis.2021.166265. PubMed PMID: 34487813. Liu Y, Wang L, Li Y, Zhong C, Wang X, Wang X, et al. HVEM in acute lymphocytic leukemia facilitates tumour immune escape by inhibiting CD8(+) T cell function. Cell Oncol (Dordr). 2024;47(5):1779-96. Epub 20240529. doi: 10.1007/s13402-024-00959-1. PubMed PMID: 38809326. Al-Kershi S, Bhayadia R, Ng M, Verboon L, Emmrich S, Gack L, et al. The stem cell-specific long noncoding RNA HOXA10-AS in the pathogenesis of KMT2A-rearranged leukemia. Blood Adv. 2019;3(24):4252-63. doi: 10.1182/bloodadvances.2019032029. PubMed PMID: 31867596; PubMed Central PMCID: PMC6929382. Zhang R, Huang H, Zhang Y, Xia Y, Huang J, Jiang C, et al. Outcomes of acute myeloid leukemia with KMT2A (MLL) rearrangement: a multicenter study of TROPHY group. Blood Cancer J. 2025;15(1):84. Epub 20250502. doi: 10.1038/s41408-025-01293-x. PubMed PMID: 40316511; PubMed Central PMCID: PMC12048516. Perner F, Gadrey JY, Armstrong SA, Kühn MWM. Targeting the Menin-KMT2A interaction in leukemia: Lessons learned and future directions. Int J Cancer. 2025. Epub 20250130. doi: 10.1002/ijc.35332. PubMed PMID: 39887730; PubMed Central PMCID: PMC12307729. Merli P, Algeri M, Galaverna F, Milano GM, Bertaina V, Biagini S, et al. Immune Modulation Properties of Zoledronic Acid on TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia. Front Immunol. 2020;11:699. Epub 20200512. doi: 10.3389/fimmu.2020.00699. PubMed PMID: 32477328; PubMed Central PMCID: PMC7235359. 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. 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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-7714797","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"comment","associatedPublications":[],"authors":[{"id":560015370,"identity":"75a4a397-c03a-423c-bbb7-0240c1b04dd0","order_by":0,"name":"Chaoban Wang","email":"","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Chaoban","middleName":"","lastName":"Wang","suffix":""},{"id":560015371,"identity":"a1464f23-3cf2-498b-a0bd-c6f067fbcb67","order_by":1,"name":"Shijing Ge","email":"","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Shijing","middleName":"","lastName":"Ge","suffix":""},{"id":560015372,"identity":"f190a655-fed8-404e-8d04-5049a836e8de","order_by":2,"name":"Gao Ju","email":"","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Gao","middleName":"","lastName":"Ju","suffix":""},{"id":560015373,"identity":"beea73f7-2a07-4ff5-bd8f-bcd52bd0e032","order_by":3,"name":"Rong Yang","email":"","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Rong","middleName":"","lastName":"Yang","suffix":""},{"id":560015374,"identity":"eb98ee82-e4e9-4edb-9a15-5e511f2c6e9d","order_by":4,"name":"xia guo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwElEQVRIiWNgGAWjYLCCBAYbCIOHBC1ppGphYDhMghb5iORjEg9qztvzz0hgfPC2jUHenJAWwxtpyQYJx24nzriRwGw4t43BcGcDIS0zcgwfJLDdTjCQSGCT5m1jSDA4QFiLwYGEf+fsgVrYfxOlRV4CaEti2wHGDUBbmInSYsDzLNkgsS85ccaZh82Sc85JGG4gaEt78jHJH9/s7Pnbkw9+eFNmI0/YFoQCxgYgIUFAPciWBsJqRsEoGAWjYKQDAAe+PXDv5L3+AAAAAElFTkSuQmCC","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":true,"prefix":"","firstName":"xia","middleName":"","lastName":"guo","suffix":""}],"badges":[],"createdAt":"2025-09-25 16:08:20","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7714797/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7714797/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":98283499,"identity":"047d1670-27fd-4e87-8962-428ebb4ed283","added_by":"auto","created_at":"2025-12-16 06:12:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":22902194,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eClinical manifestations of the patient after birth.\u003c/strong\u003e(A) “Blueberry muffin–like” skin lesions observed after birth; (B) Bone marrow smear showing a myeloid-to-erythroid ratio with 3.0% monoblasts;(C) Immunophenotyping of peripheral blood cells revealed no aberrant antigen expression; (D) Abdominal CT scan demonstrating congenital asplenia.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7714797/v1/a7645989d5511ee123defbac.png"},{"id":98283497,"identity":"6b0adfbd-a765-4b03-8050-af5b3984e197","added_by":"auto","created_at":"2025-12-16 06:12:11","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":7791693,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMICM results and extramedullary infiltration after relapse.\u003c/strong\u003e (A) Bone marrow smears revealed acute monocytic leukemia (AML-M5); (B) Immunophenotyping indicated that abnormal monocytes constituted approximately 19% of nucleated cells;(C) Karyotype analysis showed 47,XX,+?9,t(9;11)(p21;q23),del(13)(q12q22)[16]/46,XX[4]; (D) Whole-transcriptome sequencing confirmed the presence of the KMT2A-MLLT3 fusion gene.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7714797/v1/a48b909294470e17f8fabd3f.png"},{"id":98283498,"identity":"ba152f3b-0eb5-46a2-bb61-8246939c07f2","added_by":"auto","created_at":"2025-12-16 06:12:11","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3108665,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSingle-cell transcriptomic landscape of the patient.\u003c/strong\u003e(A) Hematopoietic cell subpopulations identified through UMAP dimensionality reduction and automated cell annotation;(B) CNV-based subclustering revealed leukemic progenitor cells; (C–D) Cell cycle distribution and corresponding bar plot showing the proportion of cells in each phase;(E) KEGG pathway enrichment analysis comparing leukemic and normal progenitor cells. (F) Cell–cell communication network inferred from ligand–receptor interactions; (G) Enhanced communication between leukemic cells and CD8⁺ T cells mediated by HLA-ABC and CD8A/B; (H) Strong interactions between leukemic cells and multiple antigen-presenting cell types via the ADGRE5–CD55 axis.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7714797/v1/05d070b2e2d0e232bc96901f.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Spontaneous Remission and Clonal Relapse in Congenital Infant Leukemia: Single-Cell Atlas Profiling and Curative Transplantation","fulltext":[{"header":"Background","content":"\u003cp\u003eCongenital leukemia is an extremely rare and life-threatening hematologic malignancy, typically diagnosed within the first four weeks of life. Owing to the scarcity of epidemiological data, its estimated incidence is approximately three per million births. (1) In congenital acute myeloid leukemia (AML), about two-thirds of patients present with cutaneous infiltration, which can occasionally occur in the absence of overt involvement of peripheral blood or bone marrow.(2, 3) The overall prognosis of congenital leukemia is generally dismal, particularly among patients harboring KMT2A rearrangements.\u003c/p\u003e \u003cp\u003eSpontaneous remission (SR) represents a rare phenomenon in congenital infant leukemia, defined as the disappearance of leukemic manifestations and achievement of clinical or even hematologic remission without the administration of anti-leukemic therapy. In 2018, Irene Roberts and colleagues summarized the genetic features of congenital infant AML with SR, identifying KAT6A rearrangements as the predominant subtype. By contrast, cases associated with KMT2A rearrangements have been exceedingly rare, with only five reported worldwide since the first description in 1996, and very few additional cases thereafter.(1, 3\u0026ndash;7)\u003c/p\u003e \u003cp\u003eAlthough sporadic cases of congenital leukemia with SR have been reported globally and have drawn increasing attention, their extreme rarity, the unpredictable course of remission, and frequent interruption by clinical interventions (e.g., rescue therapy) render systematic investigation difficult. As a result, compared with common forms of leukemia, SR-associated congenital leukemia lacks comprehensive molecular evidence. Clinically, such cases generally follow one of two divergent trajectories: sustained long-term remission or disease relapse. Notably, when relapse occurs, the brief interval before initiation of therapy provides a unique opportunity to obtain bone marrow tumor samples that represent the only available patient-derived, treatment-na\u0026iuml;ve material (unless the disease remains refractory despite therapy).\u003c/p\u003e \u003cp\u003eIn this report, we describe a case of congenital acute monocytic leukemia with spontaneous remission in the neonatal period, followed by relapse. At relapse, we collected bone marrow samples and performed single-cell sequencing, generating the world\u0026rsquo;s first single-cell dataset of congenital leukemia with SR. Following standard chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), the patient ultimately achieved complete remission and recovery. This case not only offers unique insights into the clonal evolution and mechanisms underlying SR in congenital leukemia but also supports the curative potential of HSCT in rare neonatal leukemia phenotypes, carrying important implications for future diagnostic and therapeutic strategies.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePostnatal Course and Spontaneous Remission\u003c/h2\u003e \u003cp\u003eWe report a term female neonate, currently 15 months of age. At birth, her Apgar scores were 5\u0026ndash;10\u0026ndash;10. She was admitted to the NICU due to respiratory distress and diffuse \u0026ldquo;blueberry muffin\u0026ndash;like\u0026rdquo; skin lesions (Fig.\u0026nbsp;1A). Complete blood count revealed WBC 108.65 \u0026times; 10^9/L, ANC 24.88 \u0026times; 10^9/L, blasts 85%, hemoglobin 166 g/L, and platelets 62 \u0026times; 10^9/L. Bone marrow smears showed an inverted myeloid-to-erythroid ratio with 3.0% monoblasts (Fig.\u0026nbsp;1B). Peripheral blood testing for leukemia fusion genes identified a KMT2A-MLLT3 fusion, while immunophenotyping of peripheral blood leukemic cells revealed no abnormal antigen expression (Fig.\u0026nbsp;1C). No hepatosplenomegaly was detected, but abdominal CT indicated congenital absence of the spleen (Fig.\u0026nbsp;1D).\u003c/p\u003e \u003cp\u003eDuring her NICU stay, she received respiratory support, anti-infective therapy, and symptomatic care, but no chemotherapy or corticosteroids. Remarkably, the cutaneous purpura and petechiae resolved, and her peripheral blood counts spontaneously normalized within two weeks. At 1 month of age, outpatient follow-up still detected the KMT2A-MLLT3 fusion gene in peripheral blood, but by 3 months, the fusion transcript had become undetectable.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRelapse, Diagnosis, and Single-Cell Sequencing Analysis\u003c/h3\u003e\n\u003cp\u003eTwo months after spontaneous remission, between 5 and 7 months of age, the patient developed recurrent rash over the lower abdomen that gradually spread across the body, accompanied by subcutaneous nodules. She also presented with a pink protrusion beneath the conjunctiva of the left eye, progressive bilateral scleral injection, and swelling of the periorbital and temporal soft tissues. She was readmitted to the Department of Pediatric Hematology. Bone marrow smears revealed acute monocytic leukemia (AML-M5). Immunophenotyping showed that abnormal monocytes accounted for ~\u0026thinsp;19% of nucleated cells. Karyotype analysis demonstrated 47,XX,+?9,t(9;11)(p21;q23),del(13)(q12q22)[16]/46,XX[4]. Whole-transcriptome sequencing confirmed the KMT2A-MLLT3 fusion and identified an NRAS mutation (Fig.\u0026nbsp;2A\u0026ndash;D).\u003c/p\u003e \u003cp\u003eThe patient also exhibited extensive extramedullary involvement. Cranial CT showed multiple patchy hyperdense lesions in the right parietal, temporal, and occipital regions, as well as the left occipital-parietal region; multiple soft tissue masses and nodules in the skull base, orbits, paranasal sinuses, and frontotemporal areas; reduced bone density and evidence of osteolytic destruction in corresponding regions (Fig.\u0026nbsp;2E\u0026ndash;F). Chest and abdominal CT revealed a lobulated soft tissue mass anterior to the upper left iliopsoas; multiple nodules on the anterior bladder wall; markedly enlarged and irregular uterus; gastric wall thickening; and enlarged, heterogeneous kidneys\u0026mdash;findings highly suggestive of leukemic infiltration (Fig.\u0026nbsp;2G\u0026ndash;H).\u003c/p\u003e \u003cp\u003eBone marrow aspirates were collected prior to chemotherapy for single-cell RNA sequencing. CNV-based sub-clustering identified leukemic progenitors (Fig.\u0026nbsp;3A\u0026ndash;B). Cell-cycle scoring indicated that leukemic progenitors lacked a clear proliferative advantage compared with normal progenitors (Fig.\u0026nbsp;3C\u0026ndash;D). Notably, leukemic progenitors showed upregulation of the autophagy pathway (Fig.\u0026nbsp;3E), potentially contributing to their capacity for spontaneous remission. Furthermore, cell\u0026ndash;cell communication analysis revealed a dual immune phenotype: on one hand, leukemic progenitors suppressed multiple immune cell functions; on the other, they remained more susceptible to cytotoxic T-cell recognition. This suggests that such leukemic progenitors may exhibit incomplete immune evasion (Fig.\u0026nbsp;3F\u0026ndash;H).\u003c/p\u003e\n\u003ch3\u003eTreatment and Follow-up\u003c/h3\u003e\n\u003cp\u003eFollowing confirmation of relapse, the patient began treatment at 7 months of age with induction chemotherapy according to the CCLG-AML-2024 protocol. The first induction course consisted of venetoclax, cytarabine, homoharringtonine, and intrathecal methotrexate, cytarabine, and dexamethasone. At the end of this course (age 8 months), bone marrow smears demonstrated complete remission (CR) of AML-M5. Molecular studies showed clearance of the NRAS mutation, while KMT2A-MLLT3 transcript levels decreased to 0.04%. MRI of the head, orbits, and abdomen revealed marked resolution of previous soft tissue and lymph node lesions, with significant improvement in the uterus and kidneys and disappearance of bladder wall nodules.\u003c/p\u003e \u003cp\u003eAt 8 months of age, the patient proceeded to the second induction course with venetoclax and decitabine, plus intrathecal triple therapy. After completion (age 9 months), bone marrow examination again confirmed CR, with both KMT2A-MLLT3 fusion and single nucleotide variant (SNV) testing negative. Minimal residual disease (MRD) by flow cytometry showed no detectable abnormal cells (\u0026lt;\u0026thinsp;10⁻⁴).\u003c/p\u003e \u003cp\u003eAt 9 months of age, the patient entered the third course, consisting of liposomal mitoxantrone and cytarabine, plus intrathecal triple therapy. During this phase, she experienced severe chemotherapy-induced myelosuppression complicated by multiple soft tissue infections, perianal infection, and intracranial hemorrhage, which resolved with intensive anti-infective and supportive management. Post-treatment bone marrow examination at 11 months confirmed continued CR, with KMT2A-MLLT3 and NRAS negativity and MRD below detectable levels. A whole-body PET/CT scan showed no abnormal FDG uptake, with no evidence of residual leukemic infiltration in the eyes or elsewhere.\u003c/p\u003e \u003cp\u003eAt 11 months of age, the patient was admitted for allogeneic hematopoietic stem cell transplantation (HSCT) from a fully HLA-matched unrelated donor (10/10). Following pre-transplant conditioning, HSCT was performed at 12 months of age. By 13 months (June 12, 2025), bone marrow examination confirmed sustained CR, with MRD undetectable and both KMT2A-MLLT3 and NRAS negative.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCongenital leukemia with SR represents one of the most unusual and poorly understood conditions in pediatric hematology. SR has been most frequently reported in congenital acute myeloid leukemia (AML) cases harboring KAT6A rearrangements. By contrast, congenital AML associated with KMT2A rearrangements generally carries a dismal prognosis, and cases with SR are exceedingly rare. Since the first report in 1996, only a handful of KMT2A-rearranged congenital leukemias with SR have been described worldwide. Our case therefore adds valuable evidence to this sparse literature and, importantly, provides the world\u0026rsquo;s first single-cell sequencing dataset in this unique setting.\u003c/p\u003e \u003cp\u003eThe rarity of SR in KMT2A-rearranged congenital leukemia raises important biological questions. In our case, the patient experienced hematologic remission within two weeks of birth without chemotherapy or corticosteroids, followed by relapse at five months of age. Single-cell RNA sequencing of bone marrow at relapse offered a unique opportunity to investigate treatment-na\u0026iuml;ve leukemic progenitors. CNV-based subclustering identified distinct leukemic populations, and cell-cycle scoring revealed that leukemic progenitors lacked a clear proliferative advantage compared with their normal counterparts. This finding suggests that these malignant cells may harbor intrinsic proliferative defects, rendering them more vulnerable to spontaneous clearance.\u003c/p\u003e \u003cp\u003eFurthermore, leukemic progenitors demonstrated upregulation of autophagy pathways, a feature that may contribute to their instability and capacity for self-limiting disease. Autophagy has been increasingly recognized as a double-edged process in cancer biology, promoting either cell survival or cell death depending on the context.(8, 9) In our patient, the enrichment of autophagy signaling may have facilitated partial elimination of leukemic cells in the neonatal period, thereby contributing to SR. In addition, our analysis of cell\u0026ndash;cell communication revealed a dual immune phenotype: leukemic progenitors suppressed multiple immune functions but remained relatively susceptible to cytotoxic T-cell recognition. This incomplete immune evasion further supports the notion that SR may result from a transient balance between vulnerable leukemic clones and an activated neonatal immune system.(10, 11) Collectively, these findings provide novel mechanistic insights into how SR may occur in congenital leukemia.\u003c/p\u003e \u003cp\u003eFrom a clinical perspective, this case highlights several important lessons. First, SR does not equate to cure. Although the patient achieved rapid remission after birth, relapse occurred within months, underscoring the high recurrence risk associated with congenital leukemia, particularly those harboring KMT2A rearrangements.(12, 13) Thus, long-term molecular monitoring remains essential even in cases that appear to resolve spontaneously.(14) Second, the temporary remission window offered a rare opportunity to obtain treatment-naive leukemic samples for research. Because most congenital leukemia patients receive urgent rescue therapy at diagnosis, such samples are rarely available. The molecular insights generated from this case may therefore inform future studies into the biology of SR and potential therapeutic strategies.\u003c/p\u003e \u003cp\u003eFinally, this case reinforces the role of hematopoietic stem cell transplantation (HSCT) in the management of high-risk neonatal AML. Following relapse, our patient responded to induction chemotherapy and ultimately underwent successful allogeneic HSCT, achieving sustained complete remission. This outcome supports previous reports suggesting that HSCT can be curative in rare neonatal leukemia phenotypes, despite their otherwise poor prognosis.(15) It also extends the evidence base for HSCT applicability to cases with prior SR and relapse, a scenario not frequently documented in the literature.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur report provides several perspectives for clinical practice: congenital leukemia carries a high risk of relapse even after spontaneous remission, warranting long-term molecular monitoring. More importantly, as the first single-cell sequencing analysis of such a patient worldwide, our findings suggest that leukemic cells in this condition may harbor intrinsic defects, offering new insights into the mechanisms of spontaneous remission. In addition, the successful cure of this rare AML subtype through HSCT further supports the applicability of HSCT in this special setting.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChaoban Wang, Rong Yang : Conception and design, Collection and \u0026nbsp; assembly of data, Data analysis and interpretation; Shijing Ge, Gao Ju, Guo Xia：Conception and design, administrative support. All authors: Manuscript writing and final approval of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of West China Second Hospital of Sichuan University and followed the Declaration of Helsinki principles (Approval No. 2021YFS0028). Written informed consent was obtained from the minor(s)’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten consent for publication was obtained from all the participants involved in our study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRoberts I, Fordham NJ, Rao A, Bain BJ. Neonatal leukaemia. Br J Haematol. 2018;182(2):170-84. Epub 20180528. doi: 10.1111/bjh.15246. PubMed PMID: 29806701.\u003c/li\u003e\n\u003cli\u003eZhang IH, Zane LT, Braun BS, Maize J, Jr., Zoger S, Loh ML. Congenital leukemia cutis with subsequent development of leukemia. J Am Acad Dermatol. 2006;54(2 Suppl):S22-7. doi: 10.1016/j.jaad.2005.04.038. PubMed PMID: 16427986.\u003c/li\u003e\n\u003cli\u003eLee EG, Kim TH, Yoon MS, Lee HJ. Congenital leukemia cutis preceding acute myeloid leukemia with t(9;11)(p22;q23), MLL-MLLT3. J Dermatol. 2013;40(7):570-1. Epub 20130417. doi: 10.1111/1346-8138.12164. PubMed PMID: 23594338.\u003c/li\u003e\n\u003cli\u003eMonpoux F, Lacour JP, Hatchuel Y, Hofman P, Raynaud S, Sudaka I, et al. Congenital leukemia cutis preceding monoblastic leukemia by 3 months. Pediatr Dermatol. 1996;13(6):472-6. doi: 10.1111/j.1525-1470.1996.tb00727.x. PubMed PMID: 8987056.\u003c/li\u003e\n\u003cli\u003eBacchetta J, Douvillez B, Warin L, Girard S, Pag\u0026egrave;s MP, Rebaud P, et al. [Blueberry Muffin Baby and spontaneous remission of neonatal leukaemia]. Arch Pediatr. 2008;15(8):1315-9. Epub 20080701. doi: 10.1016/j.arcped.2008.04.030. PubMed PMID: 18595669.\u003c/li\u003e\n\u003cli\u003eJesudas R, Buck SA, Savasan S. Spontaneous remission of congenital AML with skin involvement and t(1;11)(p32;q23). Pediatr Blood Cancer. 2017;64(3). Epub 20160929. doi: 10.1002/pbc.26269. PubMed PMID: 27682159.\u003c/li\u003e\n\u003cli\u003eGy\u0026aacute;rf\u0026aacute;s T, Wintgens J, Biskup W, Oschlies I, Klapper W, Siebert R, et al. Transient spontaneous remission in congenital MLL-AF10 rearranged acute myeloid leukemia presenting with cardiorespiratory failure and meconium ileus. Mol Cell Pediatr. 2016;3(1):30. Epub 20160829. doi: 10.1186/s40348-016-0061-7. PubMed PMID: 27510896; PubMed Central PMCID: PMC5002396.\u003c/li\u003e\n\u003cli\u003eNiu X, You Q, Hou K, Tian Y, Wei P, Zhu Y, et al. Autophagy in cancer development, immune evasion, and drug resistance. Drug Resist Updat. 2025;78:101170. Epub 20241115. doi: 10.1016/j.drup.2024.101170. PubMed PMID: 39603146.\u003c/li\u003e\n\u003cli\u003eHaghi A, Mohammadi Kian M, Salemi M, Eghdami MR, Nikbakht M. The Question of Survival or Death: What Is the Role of Autophagy in Acute Myeloid Leukemia (AML)? Int J Hematol Oncol Stem Cell Res. 2022;16(4):250-63. doi: 10.18502/ijhoscr.v16i4.10883. PubMed PMID: 36883106; PubMed Central PMCID: PMC9985813.\u003c/li\u003e\n\u003cli\u003eChen Y, Gibson SB. Three dimensions of autophagy in regulating tumor growth: cell survival/death, cell proliferation, and tumor dormancy. Biochim Biophys Acta Mol Basis Dis. 2021;1867(12):166265. Epub 20210904. doi: 10.1016/j.bbadis.2021.166265. PubMed PMID: 34487813.\u003c/li\u003e\n\u003cli\u003eLiu Y, Wang L, Li Y, Zhong C, Wang X, Wang X, et al. HVEM in acute lymphocytic leukemia facilitates tumour immune escape by inhibiting CD8(+) T cell function. Cell Oncol (Dordr). 2024;47(5):1779-96. Epub 20240529. doi: 10.1007/s13402-024-00959-1. PubMed PMID: 38809326.\u003c/li\u003e\n\u003cli\u003eAl-Kershi S, Bhayadia R, Ng M, Verboon L, Emmrich S, Gack L, et al. The stem cell-specific long noncoding RNA HOXA10-AS in the pathogenesis of KMT2A-rearranged leukemia. Blood Adv. 2019;3(24):4252-63. doi: 10.1182/bloodadvances.2019032029. 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Immune Modulation Properties of Zoledronic Acid on TcR\u0026gamma;\u0026delta; T-Lymphocytes After TcR\u0026alpha;\u0026beta;/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia. Front Immunol. 2020;11:699. Epub 20200512. doi: 10.3389/fimmu.2020.00699. PubMed PMID: 32477328; PubMed Central PMCID: PMC7235359.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"","lastPublishedDoi":"10.21203/rs.3.rs-7714797/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7714797/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCongenital leukemia is an exceptionally rare malignancy with an incidence below five per million births and poor prognosis, especially in cases with KMT2A rearrangements. Spontaneous remission (SR) is an uncommon phenomenon; since 1996, only five SR cases with KMT2A rearrangements have been reported worldwide. We describe a neonate with congenital AML-M5 carrying a KMT2A-MLLT3 fusion, who achieved SR without chemotherapy but relapsed at 5 months with extensive extramedullary disease. At relapse, we performed the world\u0026rsquo;s first single-cell transcriptomic sequencing of SR-associated congenital leukemia.\u003c/p\u003e \u003cp\u003eAnalysis showed no proliferative advantage in leukemic progenitors but marked autophagy upregulation and an incomplete immune evasion phenotype, suggesting transient dormancy and partial susceptibility to cytotoxic T-cell surveillance. The patient subsequently achieved molecular remission with CCLG-AML-2024 chemotherapy and remained disease-free following matched unrelated HSCT at 12 months.\u003c/p\u003e \u003cp\u003eThis case highlights the fragile balance between leukemic clones and host immunity in early life, suggesting autophagy activation and immune sensitivity as natural restraints on leukemogenesis. It emphasizes that SR represents a temporary pause rather than cure, requiring close molecular monitoring, and provides the first single-cell atlas of SR-type congenital leukemia, offering new directions for immunomodulatory and autophagy-targeted therapies in high-risk KMT2A-rearranged leukemia.\u003c/p\u003e","manuscriptTitle":"Spontaneous Remission and Clonal Relapse in Congenital Infant Leukemia: Single-Cell Atlas Profiling and Curative Transplantation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-16 06:12:06","doi":"10.21203/rs.3.rs-7714797/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":"19397fa0-f349-446b-97c1-7c8c71dc135f","owner":[],"postedDate":"December 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-16T06:12:06+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-16 06:12:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7714797","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7714797","identity":"rs-7714797","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}