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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-03-0767.
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Blood, 1 March 2003, Vol. 101, No. 5, pp. 1759-1768
HEMATOPOIESIS
High-level ectopic HOXB4 expression confers a profound in vivo
competitive growth advantage on human cord blood
CD34+ cells, but impairs lymphomyeloid
differentiation
Bernhard Schiedlmeier,
Hannes Klump,
Elke Will,
Gökhan Arman-Kalcek,
Zhixiong Li,
Zheng Wang,
Andreas Rimek,
Jutta Friel,
Christopher Baum, and
Wolfram Ostertag
From the Heinrich-Pette-Institute, Department of Cell
and Virus Genetics, Hamburg, Germany; and the Hannover
Medical School, Department of Hematology and Oncology, Hannover,
Germany.
Ectopic retroviral expression of homeobox B4
(HOXB4) causes an accelerated and enhanced regeneration
of murine hematopoietic stem cells (HSCs) and is not known to
compromise any program of lineage differentiation. However, HOXB4
expression levels for expansion of human stem cells have still
to be established. To test the proposed hypothesis that HOXB4 could
become a prime tool for in vivo expansion of genetically modified human
HSCs, we retrovirally overexpressed HOXB4 in purified cord blood (CB)
CD34+ cells together with green fluorescent protein
(GFP) as a reporter protein, and evaluated the impact of
ectopic HOXB4 expression on proliferation and differentiation in vitro
and in vivo. When injected separately into nonobese
diabetic-severe combined immunodeficient (NOD/SCID) mice or in
competition with control vector-transduced cells, HOXB4-overexpressing
cord blood CD34+ cells had a selective growth advantage in
vivo, which resulted in a marked enhancement of the
primitive CD34+ subpopulation (P = .01).
However, high HOXB4 expression substantially impaired the
myeloerythroid differentiation program, and this was reflected
in a severe reduction of erythroid and myeloid progenitors in vitro
(P < .03) and in vivo (P = .01).
Furthermore, HOXB4 overexpression also significantly reduced B-cell
output (P < .01). These results show for the first time
unwanted side effects of ectopic HOXB4 expression and therefore
underscore the need to carefully determine the therapeutic window of
HOXB4 expression levels before initializing clinical trials.
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