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Genomic Instability Resulting from Blm Deficiency Compromises Development, Maintenance, and Function of the B Cell Lineage¹

Holger Babbe^2,*, Jennifer McMenamin^*, Elias Hobeika, Jing Wang, Scott J. Rodig, Michael Reth and Philip Leder^*

^* Department of Genetics, Harvard Medical School, Boston, MA 02115; Max Planck Institute for Immunobiology and Centre for Biological Signalling Studies, Faculty of Biology, Albert-Ludwigs University of Freiburg, Freiburg, Germany; Immune Disease Institute, Harvard Medical School, Boston, MA 02115; and Department of Pathology, Brigham & Women’s Hospital, Boston, MA 02115

The RecQ family helicase BLM is critically involved in the maintenance of genomic stability, and BLM mutation causes the heritable disorder Bloom’s syndrome. Affected individuals suffer from a predisposition to a multitude of cancer types and an ill-defined immunodeficiency involving low serum Ab titers. To investigate its role in B cell biology, we inactivated murine Blm specifically in B lymphocytes in vivo. Numbers of developing B lymphoid cells in the bone marrow and mature B cells in the periphery were drastically reduced upon Blm inactivation. Of the major peripheral B cell subsets, B1a cells were most prominently affected. In the sera of Blm-deficient naive mice, concentrations of all Ig isotypes were low, particularly IgG3. Specific IgG Ab responses upon immunization were poor and mutant B cells exhibited a generally reduced Ab class switch capacity in vitro. We did not find evidence for a crucial role of Blm in the mechanism of class switch recombination. However, a modest shift toward microhomology-mediated switch junction formation was observed in Blm-deficient B cells. Finally, a cohort of p53-deficient, conditional Blm knockout mice revealed an increased propensity for B cell lymphoma development. Impaired cell cycle progression and survival as well as high rates of chromosomal structural abnormalities in mutant B cell blasts were identified as the basis for the observed effects. Collectively, our data highlight the importance of BLM-dependent genome surveillance for B cell immunity by ensuring proper development and function of the various B cell subsets while counteracting lymphomagenesis.

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 in part by the Deutsche Forschungsgemeinschaft (SFB620, Teilprojekt B5) to M.R. and grants from the National Institutes of Health (to J.W.).

² Address correspondence and reprint requests to Dr. Holger Babbe, Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail address: hbabbe{at}genetics.med.harvard.edu

³ Abbreviations used in this paper: CSR, class switch recombination; BS, Bloom’s syndrome; AFC, Ab-forming cell; Fr., Hardy fraction; FO, follicular; MZ, marginal zone; TD, T cell-dependent; TI, T cell-independent; DSB, double strand break; S region, switch region; AID, activation-induced cytidine deaminase; floxed, loxP-flanked; PNA, peanut agglutinin; GC, germinal center; GL, germline; PS, postswitch.