Open AccessASXL2 regulates hematopoiesis in mice and its deficiency promotes myeloid expansion
Author(s) -
Vikas Madan,
Han Lin,
Norimichi Hattori,
Weoi Woon Teoh,
Anand Mayakonda,
Qiao-Yang Sun,
Ling-Wen Ding,
Hazimah Binte Mohd Nordin,
Su Lin Lim,
S. Pavithra,
Pushkar Dakle,
Janani Sundaresan,
Ngan Doan,
Masashi Sanada,
Aiko SatoOtsubo,
Manja Meggendorfer,
Henry Yang,
Jonathan Said,
Seishi Ogawa,
Torsten Haferlach,
DerCherng Liang,
LeeYung Shih,
Tsuyoshi Nakamaki,
Q. Tian Wang,
H. Phillip Koeffler
Publication year - 2018
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2018.189928
Subject(s) - haematopoiesis , myeloid , biology , runx1 , cancer research , myeloid leukemia , leukemia , immunology , stem cell , genetics
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.