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Cell Rep. 2019 Jan 2;26(1):108-118.e4. doi: 10.1016/j.celrep.2018.12.030.

Impaired Expression of Rearranged Immunoglobulin Genes and Premature p53 Activation Block B Cell Development in BMI1 Null Mice.

Author information

1
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
2
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
3
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
4
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Department of Urology, New York University School of Medicine, New York, NY 10016, USA; Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA. Electronic address: gregory.david@nyumc.org.

Abstract

B cell development is a highly regulated process that requires stepwise rearrangement of immunoglobulin genes to generate a functional B cell receptor (BCR). The polycomb group protein BMI1 is required for B cell development, but its function in developing B cells remains poorly defined. We demonstrate that BMI1 functions in a cell-autonomous manner at two stages during early B cell development. First, loss of BMI1 results in a differentiation block at the pro-B cell to pre-B cell transition due to the inability of BMI1-deficient cells to transcribe newly rearranged Igh genes. Accordingly, introduction of a pre-rearranged Igh allele partially restored B cell development in Bmi1-/- mice. In addition, BMI1 is required to prevent premature p53 signaling, and as a consequence, Bmi1-/- large pre-B cells fail to properly proliferate. Altogether, our results clarify the role of BMI1 in early B cell development and uncover an unexpected function of BMI1 during VDJ recombination.

KEYWORDS:

B cell development; B lymphocytes; BMI1; VDJ recombination; heavy chain; immunoglobulin; p53 signaling; polycomb; pre-B cell proliferation

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