ASXL2 regulates hematopoiesis in mice and its deficiency promotes myeloid expansion.

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 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.

• Authors: 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
• Journal: Haematologica (Haematologica) Vol. 103 Issue 12 Pg. 1980-1990 (12 2018) ISSN: 1592-8721 [Electronic] Italy
• PMID: 30093396 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© 2018 Ferrata Storti Foundation.

Chemical References

• ASXL2 protein, mouse
• Repressor Proteins

Topics

• Acute Disease
• Animals
• Cell Differentiation (genetics)
• Cell Proliferation (genetics)
• Gene Expression Profiling (methods)
• Hematopoiesis (genetics)
• Humans
• Leukemia, Myeloid (genetics, pathology)
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Cells (metabolism)
• Myelopoiesis (genetics)
• Repressor Proteins (genetics)