TY - JOUR
T1 - ASXL2 regulates hematopoiesis in mice and its deficiency promotes myeloid expansion
AU - Madan, Vikas
AU - Han, Lin
AU - Hattori, Norimichi
AU - Woon Teoh, Weoi
AU - Mayakonda, Anand
AU - Sun, Qiao Yang
AU - Ding, Ling Wen
AU - Mohd Nordin, Hazimah Binte
AU - Lim, Su Lin
AU - Shyamsunder, Pavithra
AU - Dakle, Pushkar
AU - Sundaresan, Janani
AU - Doan, Ngan B.
AU - Sanada, Masashi
AU - Sato-Otsubo, Aiko
AU - Meggendorfer, Manja
AU - Yang, Henry
AU - Said, Jonathan W.
AU - Ogawa, Seishi
AU - Haferlach, Torsten
AU - Liang, Der Cherng
AU - Shih, Lee Yung
AU - Nakamaki, Tsuyoshi
AU - Wang, Q. Tian
AU - Koeffler, H. Phillip
N1 - Publisher Copyright:
© 2018 Ferrata Storti Foundation.
PY - 2018/11/30
Y1 - 2018/11/30
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85060861035
U2 - 10.3324/haematol.2018.189928
DO - 10.3324/haematol.2018.189928
M3 - 文章
C2 - 30093396
AN - SCOPUS:85060861035
SN - 0390-6078
VL - 103
SP - 1980
EP - 1990
JO - Haematologica
JF - Haematologica
IS - 12
ER -
