DOCK2 Expression Affects Leukemogenesis and Disease Progression in a Murine Model of FLT3/ITD Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm characterized by clonal expansion of myeloid blasts. The FMS-like tyrosine kinase-3 (FLT3) receptor gene is the most commonly mutated gene in AML, and an internal tandem duplication (ITD) mutation portends a poor prognosis. FLT3/ITD activates Rac1 GTPase, and both proteins play key roles in DNA damage response (DDR). Disease progression in FLT3/ITD AML is often heralded by copy-neutral loss of heterozygosity (CN-LOH) at the FLT3 locus, which is typically caused by duplication of the mutant allele through homologous recombination with loss of the wild-type (WT) allele. We previously identified dedicator of cytokinesis 2 (DOCK2) as a FLT3/ITD-interacting protein. The DOCK family of proteins acts as guanine nucleotide exchange factors for the Rho family of GTPases, including Rac1. Expression of DOCK2 is limited to hematopoietic cells, and it is expressed in leukemic blasts in FLT3/ITD AML. Knockdown of DOCK2 in FLT3/ITD cell lines results in reduced Rac1 activity, decreased expression and activity of FLT3 and DDR factors, and increased sensitivity to cytarabine. In this study, we used mouse models to further investigate the relationship between DOCK2 and FLT3/ITD. Mice with a Dock2 mutation (Dock2/Hsd) that results in a marked reduction in Dock2 expression were bred with mice that carry a Flt3/ITD mutation (Flt3+/ITD). Quantitative PCR of mouse bone marrow (BM) revealed that homozygous expression of Dock2/Hsd mar…