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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 519-528
Constitutive HOXA5 Expression Inhibits Erythropoiesis and
Increases Myelopoiesis From Human Hematopoietic Progenitors
Gay M. Crooks,
John Fuller,
Denise Petersen,
Parvin Izadi,
Punam Malik,
Paul K. Pattengale,
Donald B. Kohn, and
Judith C. Gasson
From the Division of Research Immunology and Bone Marrow
Transplantation, Department of Pathology, and Division of
Hematology/Oncology, Childrens Hospital Los Angeles, Los Angeles, CA;
and the Department of Biological Chemistry, University of California at
Los Angeles, Los Angeles, CA.
The role of the homeobox gene HOXA5 in normal human
hematopoiesis was studied by constitutively expressing the
HOXA5 cDNA in CD34+ and
CD34+CD38 cells from bone marrow and cord
blood. By using retroviral vectors that contained both HOXA5
and a cell surface marker gene, pure populations of progenitors that
expressed the transgene were obtained for analysis of differentiation
patterns. Based on both immunophenotypic and morphological analysis of
cultures from transduced CD34+ cells, HOXA5
expression caused a significant shift toward myeloid differentiation
and away from erythroid differentiation in comparison to
CD34+ cells transduced with Control vectors (P
= .001, n = 15 for immunophenotypic analysis; and P < .0001, n = 19 for morphological analysis). Transduction of more
primitive progenitors (CD34+CD38 cells)
resulted in a significantly greater effect on differentiation than did
transduction of the largely committed CD34+ population
(P = .006 for difference between HOXA5 effect on
CD34+ v CD34+CD38
cells). Erythroid progenitors (burst-forming unit-erythroid
[BFU-E]) were significantly decreased in frequency among
progenitors transduced with the HOXA5 vector (P = .016, n = 7), with no reduction in total CFU numbers. Clonal analysis
of single cells transduced with HOXA5 or control vectors
(cultured in erythroid culture conditions) showed that HOXA5
expression prevented erythroid differentiation and produced clones with
a preponderance of undifferentiated blasts. These studies show that
constitutive expression of HOXA5 inhibits human erythropoiesis
and promotes myelopoiesis. The reciprocal inhibition of erythropoiesis
and promotion of myelopoiesis in the absence of any demonstrable effect
on proliferation suggests that HOXA5 diverts differentiation at
a mulitpotent progenitor stage away from the erythroid toward the
myeloid pathway.
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