Characterization of HOX gene expression during myelopoiesis: Role of HOX A5 in lineage commitment and maturation

During the process of normal hematopoiesis, proliferation is tightly linked to maturation. The molecular mechanisms that lead to production of mature effector cells with a variety of phenotypes and functions from a single mul tipotent progenitor are only beginning to be elucidated. It is important to determine how these maturation events are regulated at the molecular level , because this will provide significant insights into the process of normal hematopoiesis as well as leukemogenesis. Transcription factors containing the highly conserved homeobox motif show considerable promise as potential regulators of hematopoietic maturation events. In this study, we focused on identification and characterization of homeobox genes of the HOX family th at are important in regulating normal human myeloid differentiation induced by the hematopoietic growth factor, granulocyte-macrophage colony-stimulat ing factor (GM-CSF), We have identified three homeobox genes, HOX A5, HOX B 6, and HOX B7, which are expressed during early myelopoiesis. Treating bone marrow cells with antisense oligodeoxynucleotides to HOX A5 resulted in in hibition of granulocytic/monocytic hematopoiesis and increased the generati on of erythroid progenitors. Also, overexpression of HOX A5 inhibited eryth roid differentiation of the K562 cell line. Based on these observations, we propose that HOX A5 functions as an important regulator of hematopoietic l ineage determination and maturation. (C) 1999 by The American Society of He matology.