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

• Published in: Blood Vol. 104; no. 8; pp. 2307 - 2314
• Main Authors: Beslu, Nathalie, Krosl, Jana, Laurin, Mélanie, Mayotte, Nadine, Humphries, Keith R., Sauvageau, Guy
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15-10-2004; The Americain Society of Hematology
• 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; Human; Cell proliferation; Stem cell; Rodentia; Hematopoietic cell; Gene overexpression; Molecular interaction; Biological activity; Vertebrata; Mammalia; Mouse; Hematopoiesis; Animal; DNA; Homeotic gene; Bone marrow; Mutation; Molecular biology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-04-1653

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.