ASXL2 regulates hematopoiesis in mice and its deficiency promotes myeloid expansion
Vikas Madan,
Lin Han,
Norimichi Hattori,
Weoi Woon Teoh,
Anand Mayakonda,
Qiao-Yang Sun,
Ling-Wen Ding,
Hazimah Binte Mohd Nordin,
Su Lin Lim,
Pavithra Shyamsunder,
Pushkar Dakle,
Janani Sundaresan,
Ngan B. Doan,
Masashi Sanada,
Aiko Sato-Otsubo,
Manja Meggendorfer,
Henry Yang,
Jonathan W. Said,
Seishi Ogawa,
Torsten Haferlach,
Der-Cherng Liang,
Lee-Yung Shih,
Tsuyoshi Nakamaki,
Q. Tian Wang,
H. Phillip Koeffler
Affiliations
Vikas Madan
Cancer Science Institute of Singapore, National University of Singapore
Lin Han
Cancer Science Institute of Singapore, National University of Singapore;Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
Norimichi Hattori
Cancer Science Institute of Singapore, National University of Singapore;Division of Hematology, Department of Medicine, School of Medicine, Showa University, Shinagawa-Ku, Tokyo, Japan
Weoi Woon Teoh
Cancer Science Institute of Singapore, National University of Singapore
Anand Mayakonda
Cancer Science Institute of Singapore, National University of Singapore
Qiao-Yang Sun
Cancer Science Institute of Singapore, National University of Singapore
Ling-Wen Ding
Cancer Science Institute of Singapore, National University of Singapore
Hazimah Binte Mohd Nordin
Cancer Science Institute of Singapore, National University of Singapore
Su Lin Lim
Cancer Science Institute of Singapore, National University of Singapore
Pavithra Shyamsunder
Cancer Science Institute of Singapore, National University of Singapore
Pushkar Dakle
Cancer Science Institute of Singapore, National University of Singapore
Janani Sundaresan
Cancer Science Institute of Singapore, National University of Singapore
Ngan B. Doan
Department of Pathology and Laboratory Medicine, Santa Monica-University of California-Los Angeles Medical Center, Los Angeles, CA, USA
Masashi Sanada
Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Japan;Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Japan
Aiko Sato-Otsubo
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Japan
Manja Meggendorfer
MLL Munich Leukemia Laboratory, Germany
Henry Yang
Cancer Science Institute of Singapore, National University of Singapore
Jonathan W. Said
Department of Pathology and Laboratory Medicine, Santa Monica-University of California-Los Angeles Medical Center, Los Angeles, CA, USA
Seishi Ogawa
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Japan
Torsten Haferlach
MLL Munich Leukemia Laboratory, Germany
Der-Cherng Liang
Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan
Lee-Yung Shih
Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
Tsuyoshi Nakamaki
Division of Hematology, Department of Medicine, School of Medicine, Showa University, Shinagawa-Ku, Tokyo, Japan
Q. Tian Wang
Department of Biological Sciences, University of Illinois at Chicago, IL, USA
H. Phillip Koeffler
Cancer Science Institute of Singapore, National University of Singapore;Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, CA, USA;Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), National University Hospital, Singapore
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 perturbations affecting, not only myeloid and erythroid differentiation, but also maturation of lymphoid cells. Overall, these findings establish a critical role for ASXL2 in maintaining steady state hematopoiesis, and provide insights into how its loss primes the expansion of myeloid cells.
