Lineage-Specific Regulation of Hematopoiesis by HOX-B8 (HOX-2.4): Inhibition of Granulocytic Differentiation and Potentiation of Monocytic Differentiation

Abstract

AbstractHomeobox proteins comprise a major class of transcription factors, which have been implicated in normal hematopoiesis and leukemogenesis. Notable in this context is the homeobox gene HOX-B8 (formerly known as HOX-2.4), which was shown to cooperate with hematokines to induce leukemia, and to enhance self-renewal of immature myeloid progenitors when expressed alone. How HOX-B8 may affect lineage specific development of hematopoietic progenitor cells is unknown. Here it is shown that ectopic expression of HOX-B8 specifically inhibited dimethyl sulfoxide (DMSO)-induced granulocytic differentiation of autonomously proliferating HL-60 myeloid progenitor cells. HOX-B8 also inhibited the granulocyte colony-stimulating factor (G-CSF )–induced granulocytic developmental program of factor dependent 32Dcl3 hematopoietic progenitors, including survival, proliferation, and differentiation, as evident by rapid apoptosis of the cells following removal of interleukin-3 (IL-3) and addition of G-CSF. In sharp contrast, HOX-B8 had no effect on macrophage differentiation of M1 and HL-60 cells induced by IL-6 and phorbol-12-myristate-13-acetate, respectively. Moreover, HOX-B8 expression endowed the 32Dcl3 cells with the ability to be induced by granulocyte-macrophage colony-stimulating factor (GM-CSF ) for terminal differentiation exclusively along the macrophage lineage; this effect was at least partially mediated via expression of the zinc finger transcription factor Egr-1. Thus, ectopic expression of HOX-B8 in hematopoietic progenitor cells appears to differentially affect lineage specific development, negatively regulating granulocyte development and positively regulating macrophage development.