ArticleNature communications2022
Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia.
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Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20citing papers in PubMed
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20 citing papers in PubMed, 34 citations in OpenAlex.
- BCL-2 and MCL1 co-inhibition enhances glucocorticoid therapy in preclinical models of infant KMT2A-rearranged acute lymphoblastic leukaemia.British journal of haematology · 2026Article
- An integrative molecular map of pediatric B-cell precursor acute lymphoblastic leukemia.Communications medicine · 2026Article
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- Intra-subtype heterogeneity shapes treatment response inHemaSphere · 2026Article
- Research Progress on the KMT2A-AFF3 Fusion Gene in Childhood Acute Lymphoblastic Leukemia: Mechanisms, Clinical Implications, and Therapeutic Strategies.Current issues in molecular biology · 2025Review
- Clinical Impact of Immunoglobulin Heavy Chain Clonality in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia.Cancer medicine · 2025Article
- Histone-, Receptor-, and Integrin-Related Gene Products and ADAM28 as Relevant to B-Cell Acute Lymphoblastic Leukemia (B-ALL).Current issues in molecular biology · 2025Article
- Disruption of cell-intrinsic PCSK9 enhances the antitumor efficacy of CD8Journal for immunotherapy of cancer · 2025Article
- Low expression of CADPS predicts poor prognosis in pediatric acute lymphoblastic leukemia without fusion genes.Biomolecules & biomedicine · 2025Article
- NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation.Leukemia · 2025Article
- Prognostic value, biological role, and mechanisms of LCN2 in childhood acute lymphoblastic leukemia.American journal of cancer research · 2025Article
- MiR-133 promotes the multidrug resistance of acute myeloid leukemia cells (HL-60/ADR) to daunorubicin.Cytotechnology · 2024Article
- MLL oncoprotein levels influence leukemia lineage identities.Nature communications · 2024Article
- Concepts in B cell acute lymphoblastic leukemia pathogenesis.Journal of leukocyte biology · 2024Review
- Metabolic Fingerprint in Childhood Acute Lymphoblastic Leukemia.Diagnostics (Basel, Switzerland) · 2024Article
- Functional relevance of circRNA aberrant expression in pediatric acute leukemia with KMT2A::AFF1 fusion.Blood advances · 2024Article
- Aberrant stem cell and developmental programs in pediatric leukemia.Frontiers in cell and developmental biology · 2024Review
- Application and research progress of single cell sequencing technology in leukemia.Frontiers in oncology · 2024Review
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Authors and funding
57 authors at 16 institutions in 4 countries.
Tomoya Isobe *Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.ORCID 0000-0002-3487-3307
Masatoshi Takagi *Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan. m.takagi.ped@tmd.ac.jp.ORCID 0000-0002-7580-9184
Aiko Sato-Otsubo *Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Akira NishimuraDepartment of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.ORCID 0000-0002-9127-807X
Genta NagaeGenome Science and Medicine Laboratory, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.ORCID 0000-0002-2929-7990
Chika YamagishiDepartment of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
Moe TamuraDivision of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
Yosuke TanakaDivision of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.ORCID 0000-0002-8538-0916
Shuhei AsadaDivision of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.ORCID 0000-0001-6116-7996
Reina TakedaDivision of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.ORCID 0000-0002-4233-8806
Akiho TsuchiyaDivision of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Xiaonan WangDepartment of Hematology, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0AW, UK.
Kenichi YoshidaDepartment of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.ORCID 0000-0003-4612-2778
Yasuhito NannyaDepartment of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Hiroo UenoDepartment of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.ORCID 0000-0001-7617-1672
Ryo AkazawaDepartment of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.ORCID 0000-0002-8770-0493
Itaru KatoDepartment of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.ORCID 0000-0002-2932-4960
Takashi MikamiDepartment of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.ORCID 0000-0003-1846-4500
Kentaro WatanabeDepartment of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Masahiro SekiguchiDepartment of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.ORCID 0000-0002-7941-9319
Masafumi SekiDepartment of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.ORCID 0000-0003-4671-7026
Shunsuke KimuraDepartment of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Mitsuteru HiwatariDepartment of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Motohiro KatoDepartment of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Shiro FukudaGenome Science and Medicine Laboratory, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.ORCID 0000-0002-0065-662X
Kenji TatsunoGenome Science and Medicine Laboratory, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.ORCID 0000-0002-3046-3941
Shuichi TsutsumiGenome Science and Medicine Laboratory, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
Akinori KanaiDepartment of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.ORCID 0000-0003-1555-6768
Toshiya InabaDepartment of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Yusuke ShiozawaDepartment of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.ORCID 0000-0001-8673-677X
Yuichi ShiraishiDivision of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan.
Kenichi ChibaDivision of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan.
Hiroko TanakaDepartment of Integrated Data Science, M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan.ORCID 0000-0001-9634-8922
Rishi S KotechaLeukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, WA, Australia.ORCID 0000-0003-1836-4075
Mark N CruickshankSchool of Biomedical Sciences, University of Western Australia, Nedlands, WA, Australia.ORCID 0000-0002-1869-1175
Fumihiko IshikawaLaboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.ORCID 0000-0002-8717-1237
Tomohiro MorioDepartment of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.ORCID 0000-0002-9259-1025
Mariko EguchiDepartment of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan.ORCID 0000-0001-8727-1732
Takao DeguchiDivision of Cancer Immunodiagnostics, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.ORCID 0000-0001-9932-4299
Nobutaka KiyokawaDepartment of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.ORCID 0000-0001-9310-2126
Yuki ArakawaDepartment of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.
Katsuyoshi KohDepartment of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.
Yuki AokiDepartment of Pediatric Oncology, National Cancer Center Japan, Tokyo, Japan.
Takashi IshiharaDepartment of Pediatrics, Nara Medical University, Kashihara, Japan.ORCID 0000-0003-1061-085X
Daisuke TomizawaDivision of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.ORCID 0000-0003-1520-7007
Takako MiyamuraDepartment of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.ORCID 0000-0002-3226-556X
Eiichi IshiiDepartment of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan.
Shuki MizutaniDepartment of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
Nicola K WilsonDepartment of Hematology, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0AW, UK.ORCID 0000-0003-0865-7333
Berthold GöttgensDepartment of Hematology, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0AW, UK.ORCID 0000-0001-6302-5705
Satoru MiyanoDepartment of Integrated Data Science, M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan.
Toshio KitamuraDivision of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.ORCID 0000-0001-7855-1767
Susumu GoyamaDivision of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.ORCID 0000-0002-9339-1826
Akihiko YokoyamaTsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan.
Hiroyuki AburataniGenome Science and Medicine Laboratory, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.ORCID 0000-0003-0438-1544
Seishi OgawaDepartment of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.ORCID 0000-0002-7778-5374
Junko TakitaDepartment of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. jtakita@kuhp.kyoto-u.ac.jp.ORCID 0000-0002-2452-6520
The University of Tokyo · JPKyoto University · JPTokyo Medical and Dental University · JPWellcome/MRC Cambridge Stem Cell Institute · GBEhime University · JPHiroshima University · JPNational Center For Child Health and Development · JPSaitama Children's Medical Center · JPMie University · JPNara Medical University · JPNational Institute of Technology, Tsuruoka College · JPRIKEN Center for Integrative Medical Sciences · JPThe Kids Research Institute Australia · AUThe University of Osaka · JPThe University of Western Australia · AUTokyo Women's Medical University · JP
Funding
Medical Research Council MC_PC_17230
Abstract
KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) represents the most refractory type of childhood leukemia. To uncover the molecular heterogeneity of this disease, we perform RNA sequencing, methylation array analysis, whole exome and targeted deep sequencing on 84 infants with KMT2A-rearranged leukemia. Our multi-omics clustering followed by single-sample and single-cell inference of hematopoietic differentiation establishes five robust integrative clusters (ICs) with different master transcription factors, fusion partners and corresponding stages of B-lymphopoietic and early hemato-endothelial development: IRX-type differentiated (IC1), IRX-type undifferentiated (IC2), HOXA-type MLLT1 (IC3), HOXA-type MLLT3 (IC4), and HOXA-type AFF1 (IC5). Importantly, our deep mutational analysis reveals that the number of RAS pathway mutations predicts prognosis and that the most refractory subgroup of IC2 possesses 100% frequency and the heaviest burden of RAS pathway mutations. Our findings highlight the previously under-appreciated intra- and inter-patient heterogeneity of KMT2A-rearranged infant ALL and provide a rationale for the future development of genomics-guided risk stratification and individualized therapy.
Indexed as
Precursor Cell Lymphoblastic Leukemia-LymphomaGene FusionHistone-Lysine N-MethyltransferaseHumansInfantMyeloid-Lymphoid Leukemia ProteinTranscription FactorsHistone-Lysine N-MethyltransferaseKMT2A protein, humanMyeloid-Lymphoid Leukemia ProteinTranscription Factors
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