Journal
BRITISH JOURNAL OF HAEMATOLOGY
Volume 175, Issue 3, Pages 476-489Publisher
WILEY
DOI: 10.1111/bjh.14247
Keywords
paediatric acute myeloid leukaemia; whole-exome sequencing; BCORL1; ASXL2; cohesin
Categories
Funding
- Ministry of Health, Labour and Welfare of Japan
- Exploratory Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan [B_24390268, C_25461611, 26461598, 26461599]
- Exploratory Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan
- Programme for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NiBio) of Japan
- Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and development [AMED_15ck0106066h0002, 16ek0109055h0003, 17ek0109055h0003, 18ek010905 5h0003]
- Grants-in-Aid for Scientific Research [26461599, 15K09653, 26461598, 15K15384, 26293242] Funding Source: KAKEN
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Acute myeloid leukaemia (AML) is a molecularly and clinically heterogeneous disease. Targeted sequencing efforts have identified several mutations with diagnostic and prognostic values in KIT, NPM1, CEBPA and FLT3 in both adult and paediatric AML. In addition, massively parallel sequencing enabled the discovery of recurrent mutations (i.e. IDH1/2 and DNMT3A) in adult AML. In this study, whole-exome sequencing (WES) of 22 paediatric AML patients revealed mutations in components of the cohesin complex (RAD21 and SMC3), BCORL1 and ASXL2 in addition to previously known gene mutations. We also revealed intratumoural heterogeneities in many patients, implicating multiple clonal evolution events in the development of AML. Furthermore, targeted deep sequencing in 182 paediatric AML patients identified three major categories of recurrently mutated genes: cohesion complex genes [STAG2, RAD21 and SMC3 in 17 patients (83%)], epigenetic regulators [ASXL1/ASXL2 in 17 patients (83%), BCOR/BCORL1 in 7 patients (34%)] and signalling molecules. We also performed WES in four patients with relapsed AML. Relapsed AML evolved from one of the subclones at the initial phase and was accompanied by many additional mutations, including common driver mutations that were absent or existed only with lower allele frequency in the diagnostic samples, indicating a multistep process causing leukaemia recurrence.
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