Dock2 deficiency compromises erythroid differentiation of hematopoietic stem cells.

Anemia is a prevalent pathological characteristic observed in a variety of hematologic disorders, predominantly resulting from impaired red blood cell production or increased erythrocyte degradation. DOCK2, a pivotal guanine nucleotide exchange factor within the DOCK protein family, is uniquely expressed within the hematopoietic system. Previous research has established that the absence of Dock2 significantly disrupts the development and function of several immune cell subsets, including T cells, B cells, NK cells, and granulocytes. However, the role of DOCK2 in erythroid development and associated biological processes remains undefined. This study aimed to investigate the biological function and molecular mechanism of DOCK2 in erythropoiesis. We generated both global and hematopoietic-specific Dock2 knockout mouse models. Results from routine blood analyses and flow cytometry consistently revealed pronounced anemic characteristics in Dock2-deficient mice. Subsequent phenotypic evaluations preliminarily ruled out excessive erythrocyte apoptosis and exacerbated hemolysis as primary contributors to the observed anemia. The developmental defect was attributed to the aberrant differentiation of bone marrow hematopoietic stem and progenitor cells (HSPCs, Lin-Sca-1+c-Kit+). Subsequent bone marrow transplantation and in vitro colony formation assays demonstrated that the deletion of Dock2 led to a compensatory increase in the number of hematopoietic stem cells, while significantly impairing their intrinsic capacity for erythroid differentiation. Integrative transcriptomic and proteomic analyses further demonstrated significant downregulation of Pepd and Prkcd in Dock2-deficient mice, yet it remains unclear whether reduced Pepd and Prkcd expression regulates erythropoiesis. Further functional experiments are necessary to validate this hypothesis in future research. In conclusion, our study identifies DOCK2 as a critical regulator for maintaining normal erythroid differentiation in hematopoietic stem cells. The absence of Dock2 disrupts hematopoietic lineage commitment, resulting in a developmental arrest of the erythroid lineage and the onset of anemia. This research advances our understanding of the regulatory mechanisms underlying erythropoiesis and the pathogenesis of anemia. Additionally, it underscores the potential of DOCK2 as a promising therapeutic target for clinical anemic conditions.