OVEREXPRESSION OF HOXA10 IN MURINE HEMATOPOIETIC-CELLS PERTURBS BOTH MYELOID AND LYMPHOID DIFFERENTIATION AND LEADS TO ACUTE MYELOID-LEUKEMIA

Multiple members of the A, B, and C clusters of Hox genes are expresse d in hematopoietic cells. Several of these Hox genes have been found t o display distinctive expression patterns, with genes located at the 3 ' side of the clusters being expressed at their highest levels in the most primitive subpopulation of human CD34(+) bone marrow cells and ge nes located at the 5' end having a broader range of expression, with d ownregulation at later stages of hematopoietic differentiation. To exp lore if these patterns reflect different functional activities, we hav e retrovirally engineered the overexpression of a 5'-located gene, HOX A10, in murine bone marrow cells and demonstrate effects strikingly di fferent from those induced by overexpression of a 3'-located gene, HOX B4. In contrast to HOXB4, which causes selective expansion of primitiv e hematopoietic cells without altering their differentiation, overexpr ession of HOXA10 profoundly perturbed myeloid and B-lymphoid different iation, The bone marrow of mice reconstituted with HOXA10-transduced b one marrow cells contained in high frequency a unique progenitor cell with megakaryocytic colony-forming ability and was virtually devoid of unilineage macrophage and pre-B-lymphoid progenitor cells derived fro m the transduced cells. Moreover, and again in contrast to HOXB4, a si gnificant proportion of HOXA10 mice developed a transplantable acute m yeloid leukemia with a latency of 19 to 50 weeks, These results thus a dd to recognition of Hox genes as important regulators of hematopoiesi s and provide important new evidence of Hox gene-specific functions th at may correlate with their normal expression pattern.