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Blood, 1 January 2002, Vol. 99, No. 1, pp. 121-129
HEMATOPOIESIS
Overexpression of the myeloid leukemia-associated
Hoxa9 gene in bone marrow cells induces stem cell
expansion
Unnur Thorsteinsdottir,
Aline Mamo,
Evert Kroon,
Lori Jerome,
Janet Bijl,
H. Jeffrey Lawrence,
Keith Humphries, and
Guy Sauvageau
From the Laboratory of Molecular Genetics of
Hemopoietic Stem Cells, Clinical Research Institute of Montréal;
Department of Medecine, Université de Montréal; and
Division of Hematology, Maisonneuve-Rosemont Hospital; both of
Montréal, Canada; V.A. Medical Center, University of San
Francisco, CA; and Terry Fox Laboratory, British Columbia Cancer
Agency, Vancouver, Canada.
Cytogenetic, genetic, and functional studies have demonstrated a
direct link between deregulated Hoxa9 expression and acute myeloid leukemia (AML). Hoxa9 overexpression in mouse bone
marrow cells invariably leads to AML within 3 to 10 months, suggesting the requirement for additional genetic events prior to AML. To gain
further insight into how Hoxa9 affects hematopoietic
development at the preleukemic stage, we have engineered its
overexpression (1) in hematopoietic stem cells using
retrovirus-mediated gene transfer and generated bone marrow
transplantation chimeras and (2) in lymphoid cells using transgenic
mice. Compared with controls, recipients of
Hoxa9-transduced cells had an about 15-fold increase in
transplantable lymphomyeloid long-term repopulating cells, indicating
the capacity for this oncogene to confer a growth advantage to
hematopoietic stem cells. In addition, overexpression of
Hoxa9 in more mature cells enhanced granulopoiesis and
partially blocked B lymphopoiesis at the pre-B-cell stage but had no
detectable effect on T lymphoid development. Interestingly, despite
specifically directing high expression of Hoxa9 in T and B
lymphoid lineages, none of the Hoxa9 transgenic mice
developed lymphoid malignancies for the observation period of more than
18 months.
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