Lineage-specific regulation of hematopoiesis by HOX-B8 (HOX-2.4): inhibition of granulocytic differentiation and potentiation of monocytic differentiation.
Homeobox 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.
Krishnaraju
K
K
Fels Institute for Cancer Research and Molecular Biology, and Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Hoffman
B
B
Liebermann
D A
DA
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics*; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000166:cytology*; D018922:HL-60 Cells; D006367:HeLa Cells; D006410:Hematopoiesis / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D009000:Monocytes / Q000166:cytology*; D009363:Neoplasm Proteins / Q000235:genetics*
D018398:Homeodomain Proteins; C095822:Hoxb8 protein, mouse; D009363:Neoplasm Proteins