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E2-2 Regulates the Expansion of Pro-B Cells and Follicular versus Marginal Zone Decisions¹

Ingela Wikström^2,*, Johan Forssell^2,*, Mario Goncalves^3,*, Francesco Colucci and Dan Holmberg^4,*

^* Department of Medical Biosciences, Umeå University, Umeå, Sweden; and Unité des Cytokines et Développement Lymphoïde, Institut Nationale de la Santé et Recherche Médicale Equipe 101, Institut Pasteur, Paris, France

The E-proteins E2A, HeLa E-box binding protein, and E2-2 constitute a class of basic helix-loop-helix transcription factors that differentially affect B cell development. E2A is by far the most investigated and appears to operate at several levels during B cell ontogeny. Less is known concerning the role of the other E-proteins. To address the role of E2-2, we have performed transfers of fetal liver (FL) cells into irradiated Rag-deficient mice. Although the transfer of E2-2-deficient cells alone can reconstitute all B cell subpopulations, albeit with a moderate reduction in cellularity, E2-2-deficient cells have a disadvantage when transferred together with wild-type cells. Cultivation of E2-2^–/– day 14.5 FL cells on stromal cells and IL-7 revealed a reduced frequency of responding B cell progenitors despite normal IL-7R surface expression. Real-time PCR analysis revealed that E2-2 mRNA expression is high at the pro-B cell stage and drops sharply at the pre-B cell stage, consistent with a role for E2-2 in pro-B cells. In contrast, E2A mRNA was most abundant in pre-B cells. Analysis of the peripheral repertoire revealed that mice reconstituted with E2-2^–/– FL cells had an increased proportion of marginal zone (MZ) B cells. Interestingly, E2-2 mRNA was elevated 2-fold (p < 0.01) in follicular compared with MZ B cells. Although E2A mRNA showed a similar tendency, the difference was not significant. Collectively, our findings indicate that E2-2 is required for optimal expansion of pro-B cells, and also influences the follicular vs MZ decision.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Swedish Cancer Foundation. M.G. was supported by funds from Fundacao para a Ciencia e a Tecnologia, Portugal. I.W., J.F., and D.H. were supported by funds from the Swedish Cancer Foundation.

² I.W. and J.F. contributed equally to this paper.

³ Mario Goncalves was deceased February 2006.

⁴ Address correspondence and reprint requests to Dr. Dan Holmberg, Department of Medical Biosciences, Division of Medical and Clinical Genetics, Umeå University, S-901 85 Umeå, Sweden. E-mail address: dan.holmberg{at}medbio.umu.se

⁵ Abbreviations used in this paper: EBF, early B cell factor; HEB, HeLa E-box binding protein; MZ, marginal zone; FL, fetal liver; Ct, comparative threshold cycle; SCL, stem cell leukemia.

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