Tyrosine Kinase-Directed Ubiquitin Ligases Cbl And Cbl-B Enforce Hematopoietic Stem Cell Quiescence By Negatively Regulating C-Kit And Flt3

Maintenance of quiescent hematopoietic stem cells (HSCs) is essential for life-long hematopoiesis. A prominent category of HSC quiescence regulators that determine HSC fate by directly interacting with niche-derived growth factors are receptor tyrosine kinases (RTKs). Cbl and Cbl-b are E3 ubiquitin ligases that are directed to activated tyrosine kinases and negatively regulate a number of cellular activation pathways. Previously, we established a conditional Cbl and Cbl-b double knockout (DKO) mouse strain using MMTV-Cre to delete floxed Cbl on a Cbl-b-null background, and identified that Cbl and Cbl-b function redundantly in controlling the growth factor-induced proliferation of HSCs. These DKO mice developed a rapidly fatal myeloproliferative disorder (MPD) accompanied by expansion of the HSC compartment. However, how the negative regulatory functions of Cbl-family proteins are integrated into HSC homeostatic program and the mechanistic basis for their role remain unknown.