Mutational landscape of pediatric acute lymphoblastic leukemia

Ling Wen Ding, Qiao Yang Sun, Kar Tong Tan, Wenwen Chien, Anand Mayakonda Thippeswamy, Allen Eng Juh Yeoh, Norihiko Kawamata, Yasunobu Nagata, Jin Fen Xiao, Xin Yi Loh, De Chen Lin, Manoj Garg, Yan Yi Jiang, Liang Xu, Su Lin Lim, Li Zhen Liu, Vikas Madan, Masashi Sanada, Lucia Torres Fernández, Hema PreethiMichael Lill, Hagop M. Kantarjian, Steven M. Kornblau, Satoru Miyano, Der Cherng Liang, Seishi Ogawa, Lee Yung Shih, Henry Yang, H. Phillip Koeffler

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)390-400
Number of pages11
JournalCancer Research
Volume77
Issue number2
DOIs
StatePublished - 15 Jan 2017
Externally publishedYes

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