PRJNA416221
ASXL2 is recurrently mutated in t(8;21) AML and regulates hematopoietic development
Chromosomal translocation t(8;21) (q22;q22) leading to generation of oncogenic RUNX1-RUNX1T1 fusion is a cytogenetic abnormality observed in about 10% of acutemyelogenous leukemia (AML). To uncover somatic mutations that cooperate with t(8;21)-driven leukemia, we used targeted and whole exome sequencing at initial diagnosis andrelapse. We identified high frequency of truncating alterations in ASXL2 along withrecurrent mutations of KIT, TET2, MGA, FLT3, and DHX15 genes in this subtype of AML.To investigate in-depth the role of ASXL2 in normal and malignant hematopoiesis, weutilized a mouse model of ASXL2 deficiency. Loss of ASXL2 caused progressivehematopoietic defects characterized by myeloid cell expansion, splenomegaly,extramedullary hematopoiesis and poor reconstitution ability of Asxl2-deficienthematopoietic stem cells in transplantation models. A parallel analysis of young and >1-year old Asxl2-deficient mice revealed age-dependent changes in the hematopoieticcompartment leading to perturbations affecting not only myeloid and erythroiddifferentiation but also maturation of lymphoid cells. Our studies also suggest thatexpression of truncated ASXL2 protein confers proliferative advantage to mouse myeloidprogenitors. Overall, these findings establish a critical role of ASXL2 in maintaining steadystate hematopoiesis and provide insights into how its loss/mutation primes leukemicgrowth of myeloid cells.