期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-32266-4
关键词
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资金
- Japan Society of Promotion of Science (JSPS) KAKENHI [JP17H04224, JP18K19467, JP19J11112, JP20H00528, JP21K19405, JP19H05656, JP19H03685, JP15K19601]
- Japan Agency for Medical Research and Development (AMED) [JP15cm0106056h0005, JP19cm0106501h0004, JP16ck0106073h0003, JP19ck0106250h0003, JP21cm0106501h0006]
- AMED Project for Cancer Research and Therapeutic Evolution (P-CREATE) [JP20cm0106509h9905, JP15cm0106139s0202, JP20cm0106572h0001]
- Practical Research for Innovative Cancer Control [JP20ck0106468h0002]
- AMED Project for Promotion of Cancer Research and Therapeutic Evolution (P-PROMOTE) [JP22ama221505h0001]
- Ministry of Education, Culture, Sports, Science and Technology of Japan (Program for Promoting Researches on the Supercomputer Fugaku) [JPMXP1020200102, hp200138]
- High Performance Computing Infrastructure System Research Project [hp160219, hp170227, hp180198, hp190158]
- Princess Takamatsu Cancer Research Fund
- Japan Foundation for Pediatric Research [18-001]
- Funai Foundation for Information Technology
This study uncovers the molecular heterogeneity of KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) through multi-omics analysis, establishes five distinct subgroups, and reveals the predictive value of RAS pathway mutations for prognosis.
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. The molecular heterogeneity of KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) remains poorly characterised. Here, the authors perform multi-omics analysis for 84 ALL patients and suggest 5 distinct subgroups for risk stratification and personalised treatment.'
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