ASXL2 regulates hematopoiesis in mice and its deficiency promotes myeloid expansion

• Published in: Haematologica (Roma) 2018-12, Vol.103 (12), p.1980-1990
• Main Authors: Madan, Vikas, Han, Lin, Hattori, Norimichi, Teoh, Weoi Woon, Mayakonda, Anand, Sun, Qiao-Yang, Ding, Ling-Wen, Binte Mohd Nordin, Hazimah, Lim, Su Lin, Shyamsunder, Pavithra, Dakle, Pushkar, Sundaresan, Janani, Doan, Ngan B, Sanada, Masashi, Sato-Otsubo, Aiko, Meggendorfer, Manja, Yang, Henry, Said, Jonathan W, Ogawa, Seishi, Haferlach, Torsten, Liang, Der-Cherng, Shih, Lee-Yung, Nakamaki, Tsuyoshi, Wang, Q Tian, Koeffler, H Phillip
• Format: Article
• Language: English
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2018.189928

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.