Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia

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

来源：Cancer Research, 2017, 77(2): 390-400.

DOI：10.1158/0008-5472.CAN-16-1303

Current standard of care for patients with pediatric acute lymphoblastic leukemia (ALL) ismainly 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.

• 出版日期2017-1-15
• 单位河北医科大学; 长春大学