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Blood, 15 April 2001, Vol. 97, No. 8, pp. 2286-2292
HEMATOPOIESIS
Overexpression of HOXA10 perturbs human
lymphomyelopoiesis in vitro and in vivo
Christian Buske,
Michaela Feuring-Buske,
Jennifer Antonchuk,
Patricia Rosten,
Donna E. Hogge,
Connie J. Eaves, and
R. Keith Humphries
From The Terry Fox Laboratory, British Columbia Cancer
Agency, and the Departments of Medicine and Medical Genetics,
University of British Columbia, Vancouver, BC, Canada.
Several studies point to multiple members of the Hox transcription
factor family as playing key roles in normal hematopoietic development,
and they link the imbalanced expression of these transcription factors,
in particular of the Abd-like A cluster HOX
genes HOXA9 and HOXA10, to
leukemogenesis. To test directly the hypothesis that HOXA10
is involved in human hematopoietic development, the gene was
retrovirally overexpressed in human highly purified
CD34+/GFP+ hematopoietic progenitor
cells derived from cord blood or fetal liver sources, and the impact of
aberrant gene expression was analyzed on differentiation and
proliferation in vitro and in vivo. HOXA10 misexpression
profoundly impaired myeloid differentiation with a higher yield of
blast cells in liquid culture and a greater than 100-fold increased
generation of blast colonies after in vitro expansion or after
replating of primary colonies first plated in methylcellulose directly
after transduction (P < .01). Furthermore, aberrant
HOXA10 expression almost completely blocked erythroid differentiation in methylcellulose (P < .02).
HOXA10 deregulation also severely perturbed the
differentiation of human progenitors in vivo, reducing B-cell
development by 70% in repopulated NOD/SCID mice and enhancing
myelopoiesis in the transduced compartment. The data provide evidence
that the balanced expression of HOXA10 is pivotal for
normal human hematopoietic development and that aberrant expression of
the gene contributes to impaired differentiation and increased
proliferation of human hematopoietic progenitor cells. These results
also provide a framework to initiate more detailed analyses of
HOX regulatory domains and HOX cofactors in the
human system in vitro and in vivo.
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