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Molecular and Cellular Biology, February 2002, p. 886-900, Vol. 22, No. 3
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.3.886-900.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Gradient of E2A Activity in B-Cell Development

Sabine Herblot,1 Peter D. Aplan,2 and Trang Hoang3*

The Clinical Research Institute of Montréal, Montréal, Québec, Canada H2W 1R7,1 Genetics Department, Medicine Branch, Division of Clinical Science, National Cancer Institute, Gaithersburg, Maryland 20877,2 Departments of Pharmacology and Biochemistry and Molecular Biology Program, University of Montréal, Québec, Canada H3C 3J73

Received 30 May 2001/ Returned for modification 10 July 2001/ Accepted 6 November 2001

The E2A locus is a frequent target of chromosomal translocations in B-cell acute lymphoblastic leukemia (B-ALL). E2A encodes two products, E12 and E47, that are part of the basic helix-loop-helix (bHLH) family of transcription factors and are central in B lineage differentiation. E2A haplo-insufficiency hinders progression through three major checkpoints in B-cell development: commitment into the B lineage, at the pro-B to pre-B transition, and in the induction of immunoglobulin M (IgM) expression required for a functional BCR. These observations underscore the importance of E2A gene dosage in B-cell development. Here we show that a higher proportion of pro-B cells in E2A+/- mice is in the cell cycle compared to that in wild-type littermates. This increase correlates with lower p21waf/cip1 levels, indicating that E2A has an antiproliferative function in B-cell progenitors. Ectopic expression in the B lineage of SCL/Tal1, a tissue-specific bHLH factor that inhibits E2A function, blocks commitment into the B lineage without affecting progression through later stages of differentiation. Furthermore, ectopic SCL expression exacerbates E2A haplo-insufficiency in B-cell differentiation, indicating that SCL genetically interacts with E2A. Taken together, these observations provide evidence for a gradient of E2A activity that increases from the pre-pro-B to the pre-B stage and suggest a model in which low levels of E2A (as in pro-B cells) are sufficient to control cell growth, while high levels (in pre-B cells) are required for cell differentiation. The antiproliferative function of E2A further suggests that in B-ALL associated with t(1;19) and t(17;19), the disruption of one E2A allele contributes to leukemogenesis, in addition to other anomalies induced by E2A fusion proteins.

* Corresponding author. Mailing address: Institut de Recherches Cliniques de Montréal, 110 Ave. des Pins Ouest, Montréal, Québec H2W 1R7, Canada. Phone: (514) 987-5588. Fax: (514) 987-5757. E-mail: hoangt{at}ircm.qc.ca.

Molecular and Cellular Biology, February 2002, p. 886-900, Vol. 22, No. 3
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.3.886-900.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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