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E4F1: a novel candidate factor for mediating BMI1 function in primitive hematopoietic cells

¹ Laboratory of Molecular Genetics of Hematopoietic Stem Cells, Institut de Recherche en Immunologie et Cancérologie (IRIC), C.P. 6128 succursale Centre-Ville, Montréal, Québec H3C 3J7, Canada; ² Laboratory of Signaling and Cell Growth, Institut de Recherche en Immunologie et Cancérologie (IRIC), C.P. 6128 succursale Centre-Ville, Montréal, Québec H3C 3J7, Canada; ³ Departments of Molecular Biology and Pharmacology, Université de Montréal, Montréal, Québec, Canada; ⁴ Department of Medicine, Division of Hematology, and Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montréal, Québec H1T, 2M4, Canada

The Polycomb group gene Bmi1 is essential for the proliferation of neural and hematopoietic stem cells. Much remains to be learned about the pathways involved in the severe hematopoietic phenotype observed in Bmi1 homozygous mutant mice except for the fact that loss of p53 or concomitant loss of p16^Ink4a and p19^Arf functions achieves only a partial rescue. Here we report the identification of E4F1, an inhibitor of cellular proliferation, as a novel BMI1-interacting partner in hematopoietic cells. We provide evidence that Bmi1 and E4f1 genetically interact in the hematopoietic compartment to regulate cellular proliferation. Most importantly, we demonstrate that reduction of E4f1 levels through RNA interference mediated knockdown is sufficient to rescue the clonogenic and repopulating ability of Bmi1^–/– hematopoietic cells up to 3 mo post-transplantation. Using cell lines and MEF, we also demonstrate that INK4A/ARF and p53 are not essential for functional interaction between Bmi1 and E4f1. Together, these findings identify E4F1 as a key modulator of BMI1 activity in primitive hematopoietic cells.

[Keywords: Polycomb; Bmi1; hematopoietic stem cell self-renewal; E4F1; senescence]

Received January 25, 2006; revised version accepted June 6, 2006.

E-MAIL guy.sauvageau{at}umontreal.ca; FAX (514) 343-7379.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1453406

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