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Haematologica 2018 Volume 103(12):1980-1990
Ferrata Storti Foundation
Hematopoiesis
ASXL2 regulates hematopoiesis in mice and its deficiency promotes myeloid expansion
Vikas Madan,1 Lin Han,1,2 Norimichi Hattori,1,3 Weoi Woon Teoh,1
Anand Mayakonda,1 Qiao-Yang Sun,1 Ling-Wen Ding,1
Hazimah Binte Mohd Nordin,1 Su Lin Lim,1 Pavithra Shyamsunder,1 Pushkar Dakle,1 Janani Sundaresan,1 Ngan B. Doan,4 Masashi Sanada,5,6 Aiko Sato-Otsubo,6 Manja Meggendorfer,7 Henry Yang,1 Jonathan W. Said,4 Seishi Ogawa,6 Torsten Haferlach,7 Der-Cherng Liang,8 Lee-Yung Shih,9 Tsuyoshi Nakamaki,3 Q. Tian Wang10 and H. Phillip Koeffler1,11,12
1Cancer Science Institute of Singapore, National University of Singapore; 2Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; 3Division of Hematology, Department of Medicine, School of Medicine, Showa University, Shinagawa-Ku, Tokyo, Japan; 4Department of Pathology and Laboratory Medicine, Santa Monica-University of California-Los Angeles Medical Center, Los Angeles, CA, USA; 5Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Japan; 6Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Japan; 7MLL Munich Leukemia Laboratory, Germany; 8Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan; 9Division of Hematology- Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan; 10Department of Biological Sciences, University of Illinois at Chicago, IL, USA; 11Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, CA, USA and 12Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), National University Hospital, Singapore
LH and NH contributed equally to this work
ABSTRACT
Chromosomal translocation t(8;21)(q22;q22) which leads to the generation of oncogenic RUNX1-RUNX1T1 (AML1-ETO) fusion is observed in approximately 10% of acute myelogenous leukemia (AML). To identify somatic mutations that co-operate 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 per- turbations affecting, not only myeloid and erythroid differentiation, but also maturation of lymphoid cells. Overall, these findings establish a crit- ical role for ASXL2 in maintaining steady state hematopoiesis, and pro- vide insights into how its loss primes the expansion of myeloid cells.
Introduction
Chromosomal translocation t(8;21) (q22;q22) is a frequent cytogenetic abnormal- ity observed in approximately 10% of acute myelogenous leukemia (AML). This rearrangement involves RUNX1 gene on chromosome 21 and RUNX1T1 gene on chromosome 8 and results in generation of oncogenic RUNX1-RUNX1T1 fusion protein (also known as AML1-ETO).1 However, expression of RUNX1-RUNX1T1 alone, either as a transgene or using viral transduction in hematopoietic cells, is insufficient to cause leukemia in mice.2-4 Loss of sex chromosome and other chro- mosomal aberrations, as well as recurrent somatic mutations of KIT, FLT3, NRAS and KRAS, are associated with t(8;21) AML.2,4 Recent high-throughput sequencing
Correspondence:
csivm@nus.edu.sg or nhattor@med.showa-u.ac.jp or sly7012@cgmh.org.tw
Received: January 31, 2018. Accepted: July 26, 2018. Pre-published: August 9, 2018.
doi:10.3324/haematol.2018.189928
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