Madan V1, Han L2, Hattori N3, Teoh WW2, Mayakonda A2, Sun QY2, Ding LW2, Binte Mohd Nordin H2, Lim SL2, Shyamsunder P2, Dakle P2, Sundaresan J2, Doan NB4, Sanada M5, Sato-Otsubo A6, Meggendorfer M7, Yang H2, Said JW4, Ogawa S6, Haferlach T7, Liang DC8, Shih LY9, Nakamaki T3, Wang QT10, Koeffler HP11.
1 Cancer Science Institute of Singapore
2 Cancer Science Institute of Singapore.
3 School of Medicine, Showa University.
4 Santa Monica-University of California-Los Angeles Medical Center.
5 National Hospital Organization Nagoya Medical Center.
6 Graduate School of Medicine, Kyoto University.
7 MLL Munich Leukemia Laboratory, Munich, Germany.
8 Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan.
9 Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
10 Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL, USA.
11 Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Chromosomal translocation t(8;21)(q22;q22) which leads to generation of oncogenic RUNX1-RUNX1T1 (AML1-ETO) fusion is observed in about 10% of acute myelogenous leukemia (AML). To uncover somatic mutations that cooperate with t(8;21)-driven leukemia, we performed whole and targeted exome sequencing of an Asian cohort at diagnosis and relapse. We identified high frequency of truncating alterations in ASXL2 along with recurrent mutations of KIT, TET2, MGA, FLT3, and DHX15 in this subtype of AML. To investigate in-depth the role of ASXL2 in normal hematopoiesis, we utilized a mouse model of ASXL2 deficiency. Loss of ASXL2 caused progressive hematopoietic defects characterized by myeloid hyperplasia, splenomegaly, extramedullary hematopoiesis and poor reconstitution ability in transplantation models. Parallel analyses of young and >1-year old Asxl2-deficient mice revealed age-dependent perturbations affecting not only myeloid and erythroid differentiation but also maturation of lymphoid cells. Overall, these findings establish a critical role of ASXL2 in maintaining steady state hematopoiesis and provide insights into how its loss primes expansion of myeloid cells.
KEYWORDS: AML1-ETO; ASXL2; Acute Myeloid Leukemia; Hematopoiesis