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

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 b...

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Bibliographic Details
Published in:Blood 2004-10, Vol.104 (8), p.2307-2314
Main Authors: Beslu, Nathalie, Krosl, Jana, Laurin, Mélanie, Mayotte, Nadine, Humphries, Keith R., Sauvageau, Guy
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cell differentiation, maturation, development, hematopoiesis
Cell Division
Cell Line
Cell physiology
DNA - metabolism
Fundamental and applied biological sciences. Psychology
Gene Expression
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - metabolism
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Mice
Molecular and cellular biology
Mutation - genetics
Protein Binding
Transcription Factors - genetics
Transcription Factors - metabolism
Tryptophan - genetics
Tryptophan - metabolism
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Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2004-04-1653