Constitutive HOXA5 expression inhibits erythropoiesis and increases myelopoiesis from human hematopoietic progenitors

The role of the homeobox gene HOXA5 in normal human hematopoiesis was studi ed by constitutively expressing the HOXA5 cDNA in CD34(+) and CD34(+)CD38(- ) cells from bone marrow and cord blood. By using retroviral vectors that c ontained both HOXA5 and a cell surface marker gene, pure populations of pro genitors that expressed the transgene were obtained for analysis of differe ntiation patterns. Based on both immunophenotypic and morphological analysi s of cultures from transduced CD34(+) cells, HOXA5 expression caused a sign ificant shift toward myeloid differentiation and away from erythroid differ entiation in comparison to CD34(+) cells transduced with Control vectors (P = .001, n = 15 for immunophenotypic analysis; and P < .0001, n = 19 for mo rphological analysis). Transduction of more primitive progenitors (CD34(+)C D38(-) cells) resulted in a significantly greater effect on differentiation than did transduction of the largely committed CD34(+) population (P = .00 6 for difference between HOXA5 effect on CD34(+) v CD34(+)CD38(-) cells). E rythroid progenitors (burst-forming unit-erythroid [BFU-E]) were significan tly decreased in frequency among progenitors transduced with the HOXA5 vect or (P = .016, n = 7), with no reduction in total CFU numbers. Clonal analys is of single cells transduced with HOXA5 or control vectors (cultured in er ythroid culture conditions) showed that HOXA5 expression prevented erythroi d differentiation and produced clones with a preponderance of undifferentia ted blasts. These studies show that constitutive expression of HOXA5 inhibi ts human erythropoiesis and promotes myelopoiesis. The reciprocal inhibitio n of erythropoiesis and promotion of myelopoiesis in the absence of any dem onstrable effect on proliferation suggests that HOXA5 diverts differentiati on at a mulitpotent progenitor stage away from the erythroid toward the mye loid pathway. (C) 1999 by The American Society of Hematology.