Ding L1, Sun QY2, Tan KT2, Chien W3, Thippeswamy AM3, Eng Juh AY3, Kawamata N3, Nagata Y4, Xiao JF3, Loh XY2, Lin DC2, Garg M5, Lim SL3, Liu LZ2, Madan V5, Jiang YY2, Xu L6, Sanada M7, Fernández LT2, Preethi H2, Lill M8, Kantarjian H9, Kornblau SM10, Miyano S11, Ogawa S12, Liang DC13, Shih LY14, Yang H3, Koeffler HP15
1Cancer science institute of Singapore, NUS, Cancer science institute of Singapore, NUS email@example.com.
2Cancer science institute of Singapore, NUS, Cancer science institute of Singapore, NUS.
3Cancer Science Institute of Singapore, National University of Singapore.
4Cancer Genomics, The University of Tokyo.
5Cancer Science Institute (CSI) of Singapore, NUS, Cancer Science Institute (CSI) of Singapore, NUS.
6National Cancer Institute,Cancer Science Institute,, National University of Singapore.
7Cancer Genomics Project, Tokyo University Hospital.
8UCLA School of Medicine, Cedars-Sinai Medical Center.
9LEUKEMIA, MD ANDERSON CANCER CENTER.
10Department of Leukemia, The University of Texas MD Anderson Cancer Center.
11Laboratory of DNA Information Analysis, Human Genome Center, Medical Science, University of Tokyo.
12Department of Pathology and Tumor biology, Graduate School of Medicine, Kyoto University.
13Department of Pediatrics, Mackay Memorial Hospital.
14Division of Hematology, Chang Gung Memorial Hospital-Linkou, Chang Gung University.
15Department of Medicine, Cedars-Sinai Medical Center.
Current standard of care for patients with pediatric acute lymphoblastic leukemia (ALL) is mainly effective, with high remission rates after treatment. However, the genetic perturbations that give rise to this disease remain largely undefined, limiting the ability to address resistant tumors or develop less toxic targeted therapies. Here we report the use of next generation sequencing to interrogate the genetic and pathogenic mechanisms of 240 pediatric ALL cases with their matched remission samples. Commonly mutated genes fell into several categories, including RAS/receptor tyrosine kinases, epigenetic regulators, transcription factors involved in lineage commitment and the p53/cell cycle pathway. Unique recurrent mutational hotspots were observed in epigenetic regulators CREBBP (R1446C/H), WHSC1 (E1099K) and the tyrosine kinase FLT3 (K663R, N676K). The mutant WHSC1 was established as a gain-of-function oncogene, while the epigenetic regulator ARID1A and transcription factor CTCF were functionally identified as potential tumor suppressors. Analysis of 28 diagnosis/relapse trio patients plus 10 relapse cases revealed four evolutionary paths and uncovered the ordering of acquisition of mutations in these patients. This study provides a detailed mutational portrait of pediatric ALL and gives insights into the molecular pathogenesis of this disease.