Characterization of HOX Gene Expression During Myelopoiesis: Role of HOX A5 in Lineage Commitment and Maturation

Abstract

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 multipotent 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 that are important in regulating normal human myeloid differentiation induced by the hematopoietic growth factor, granulocyte-macrophage colony-stimulating factor (GM-CSF). We have identified three homeobox genes, HOX A5, HOX B6, and HOX B7, which are expressed during early myelopoiesis. Treating bone marrow cells with antisense oligodeoxynucleotides to HOX A5 resulted in inhibition of granulocytic/monocytic hematopoiesis and increased the generation of erythroid progenitors. Also, overexpression of HOX A5 inhibited erythroid differentiation of the K562 cell line. Based on these observations, we propose that HOX A5 functions as an important regulator of hematopoietic lineage determination and maturation.

Bone marrow glycophorin‐positive erythroid cells of myelodysplastic patients responding to high‐dose rHuEPO therapy have a different gene expression pattern from those of nonresponders

“…Our ENRs had reduced levels of PRDX, which physiologically slows the MAPK pathway, and normal levels of the MAP2K3, MAP3K11, and TGFBR1 transcripts, which were reduced in our ERs. As the constitutive activation of the MAPK/ERK pathway and the overexpression of HOX A5 block erythroid differentiation [63,64], the fact that all of these transcripts are increased in ENRs is consistent with their observed resistance to rHuEPO-stimulation.…”

Enforced expression of HOX11 is associated with an immature phenotype in J2E erythroid cells

“…For example, overexpression of either HOXB6 or HOXA5 has been shown to inhibit erythroid differentiation in human cell lines (Shen et al , 1992; Fuller et al , 1999). Dramatic effects on the erythroid lineage have also been demonstrated by modulating the expression of HOX genes in primitive bone marrow cells or in whole mice via targeted disruption of HOX genes (Giampaolo et al , 1994; Lawrence et al , 1997; Crooks et al , 1999; Fuller et al , 1999; Kappen, 2000). However, none of these reports has documented the imposition of a more primitive erythroid phenotype in a similar manner to that shown by HOX11 in this study.…”

The role of HOX genes in normal hematopoiesis and acute leukemia

“…37 Overexpression of human HOXC4 resulted in expansion of early and committed myeloid and erythroid progenitors, 47 and knockin of human HOXA5 caused an increase in the number of myeloid progenitors and blocked erythroid differentiation. 30,31 Likewise, overexpression of HOXA10 in human cord blood or fetal liver CD34 þ hematopoietic progenitors resulted in a significant production of blast cells and myelopoiesis concomitant with a complete block of erythroid differentiation and a severe reduction in B-cell development. 36 Other HOX genes are required for the maintenance of progenitor or stem cell status and promote their proliferation, especially HOXA9 and HOXB4.…”