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 Blood, 15 October 2004, Vol. 104, No. 8, pp. 2307-2314.
Prepublished online as a Blood First Edition Paper on June 29, 2004; DOI 10.1182/blood-2004-04-1653.

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HEMATOPOIESIS

Molecular interactions involved in HOXB4-induced activation of HSC self-renewal

Nathalie Beslu, Jana Krosl, Mélanie Laurin, Nadine Mayotte, Keith R. Humphries, and Guy Sauvageau

From the Laboratory of Molecular Genetics of Hemopoietic Stem Cells, Institut de Recherches en Immunovirologie et Cancérlogie, Pavillon Roger-Gaudry, Université de Montréal; the Department of Medicine, Université de Montréal, QC, Canada; the Division of Hematology, Hospital Maisonneuve-Rosemont, Montréal, QC, Canada; and the Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.

HOXB4 overexpression induces unique in vivo and in vitro expansion of hemopoietic stem cells (HSCs) without causing leukemia. Very little is known about the molecular basis underlying HOXB4-induced HSC self-renewal. We now report the in vitro proliferation and in vivo expansion capacity of primary bone marrow (BM) cells engineered to overexpress selected HOXB4 point mutants lacking either the capacity to directly bind DNA (HOXB4(A)), or to cooperate with members of the PBX family (HOXB4(W->G)) in DNA binding. The DNA binding–incompetent HOXB4 mutant failed to enhance the proliferation activity of transduced BM populations in vitro and HSC expansion in vivo. In contrast, the HOXB4(W->G) mutant conferred a pronounced in vitro proliferation advantage to the transduced BM populations, and dramatically enhanced their in vivo regenerative potential. We also demonstrate a correlation between HOXB4 protein levels and in vitro proliferative capacity of primary BM cells. Our observations thus suggest that the capacity of HOXB4 to induce HSC expansions is DNA-binding dependent and does not require direct HOX/PBX interaction, and sets the stage for identifying HOXB4-dependent targets involved in HSC expansion.


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Related Article in Blood Online:

Stem cell expansion: success and complexities
Stefan Karlsson
Blood 2004 104: 2210-2211. [Full Text] [PDF]



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