The HOX homeodomain proteins are key regulators of hematopoiesis. HOX genes are expressed in primitive hematopoietic cells, and their prompt downregulation is associated with hematopoietic differentiation and maturation. Although transcriptional inactivation of HOX genes during hematopoietic differentiation has been established, little is known about the biochemical mechanisms underlying the subsequent removal of HOX proteins. We have previously shown that the CUL-4A ubiquitin ligase controls the stability of HOXA9 by promoting its ubiquitination and proteasome-dependent degradation. Interfering with CUL-4A biosynthesis results in altered HOXA9 protein levels, which is mirrored by the impairment of myeloid progenitor cells to undergo proper terminal differentiation into granulocytes. Here we show that additional HOX proteins are also subjected to CUL-4A-mediated ubiquitination and destruction. Consistently, the HOX homeodomain, which is highly conserved among all HOX proteins, is responsible for controlling their stability. Silencing of CUL-4A by RNA-mediated interference in human umbilical cord blood CD34+ cells significantly perturbs their self-renewal, expansion, and differentiation properties. These results reveal a novel regulatory mechanism of hematopoiesis by ubiquitin-dependent proteolysis. Recent studies on the biochemical mechanisms underlying HOX ubiquitination and by which leukemogenic HOX fusions evade CUL-4A-dependent degradation will be presented.

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