Functional characterization of asymmetric cell division associated genes in hematopoietic stem cells and bone marrow failure syndromes

Abstract

Hematopoietic stem cells (HSCs) are critical to the development of the hematopoietic system during ontogeny and maintaining hematopoiesis under steady-state. Several genes implicated in asymmetric cell division (ACD) have been found to influence HSC self-renewal in normal hematopoiesis and various leukemias. From a separate survey of genes associated with ACD, I now present the results from dedicated functional studies on two genes – Arhgef2 and Staufen1 – in HSCs and identify their potential contributions to benign hematopoietic disorders. Specifically, I present evidence that demonstrates a conserved role of Arhgef2 in orienting HSC division, the loss of which leads to HSC exhaustion that may underlie and contribute to the pathogenesis of Shwachman-Diamond syndrome. I also identify Staufen1 as a critical RNA-binding protein (RBP) in HSC function, downregulation of which elicits expression signatures consistent with clinical anemias reminiscent of aplastic anemia and/or paroxysmal nocturnal hemoglobinuria. I end by reviewing how RBPs function in HSCs and discuss future research directions that could further elucidate how bone marrow failure syndromes arise at the stem cell level.