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Nat Immunol. 2017 Aug;18(8):911-920. doi: 10.1038/ni.3774. Epub 2017 Jun 19.

The BTG2-PRMT1 module limits pre-B cell expansion by regulating the CDK4-Cyclin-D3 complex.

Author information

1
Department for Molecular Immunology, Faculty of Biology, Albert-Ludwigs University of Freiburg, Freiburg, Germany.
2
Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
3
Spemann Graduate School of Biology and Medicine (SGBM) Albert-Ludwigs University of Freiburg, Freiburg, Germany.
4
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
5
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
6
Department of Immunology and Pathology, Monash University, Melbourne, Australia.
7
BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs University of Freiburg, Freiburg, Germany.
8
Department of Biochemistry and Functional Proteomics, Faculty of Biology, Albert-Ludwigs University of Freiburg, Freiburg, Germany.
9
Center of Chronic Immunodeficiency CCI, University Clinics and Medical Faculty, Freiburg, Germany.
10
Institute of Immunology, University Hospital Ulm, Ulm, Germany.

Abstract

Developing pre-B cells in the bone marrow alternate between proliferation and differentiation phases. We found that protein arginine methyl transferase 1 (PRMT1) and B cell translocation gene 2 (BTG2) are critical components of the pre-B cell differentiation program. The BTG2-PRMT1 module induced a cell-cycle arrest of pre-B cells that was accompanied by re-expression of Rag1 and Rag2 and the onset of immunoglobulin light chain gene rearrangements. We found that PRMT1 methylated cyclin-dependent kinase 4 (CDK4), thereby preventing the formation of a CDK4-Cyclin-D3 complex and cell cycle progression. Moreover, BTG2 in concert with PRMT1 efficiently blocked the proliferation of BCR-ABL1-transformed pre-B cells in vitro and in vivo. Our results identify a key molecular mechanism by which the BTG2-PRMT1 module regulates pre-B cell differentiation and inhibits pre-B cell leukemogenesis.

PMID:
28628091
DOI:
10.1038/ni.3774
[Indexed for MEDLINE]

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