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

Elmar Dolezal; Simona Infantino; Friedel Drepper; Theresa Börsig; Aparajita Singh; Thomas Wossning; Gina J Fiala; Susana Minguet; Bettina Warscheid; David M Tarlinton; Hassan Jumaa; David Medgyesi; Michael Reth

doi:10.1038/ni.3774

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

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

Authors

Elmar Dolezal^{1

2

3}, Simona Infantino^{4

5

6}, Friedel Drepper^{7

8}, Theresa Börsig¹, Aparajita Singh^{1

2}, Thomas Wossning², Gina J Fiala^{1

7

9}, Susana Minguet^{1

7

9}, Bettina Warscheid^{7

8}, David M Tarlinton^{4

5

6}, Hassan Jumaa^{1

7

10}, David Medgyesi^{1

2

7}, Michael Reth^{1

2

7}

Affiliations

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.

PMID: 28628091
DOI: 10.1038/ni.3774

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.

MeSH terms

Animals
Cell Cycle Checkpoints
Cell Differentiation / genetics
Cell Proliferation / genetics*
Cyclin D3 / metabolism*
Cyclin-Dependent Kinase 4 / metabolism*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Flow Cytometry
Gene Knockdown Techniques
Gene Rearrangement, B-Lymphocyte / genetics
Genes, abl / genetics
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Immediate-Early Proteins / genetics*
Immediate-Early Proteins / metabolism
Immunoglobulin Light Chains / genetics
Lymphopoiesis / genetics*
Mass Spectrometry
Mice
Precursor Cells, B-Lymphoid / cytology
Precursor Cells, B-Lymphoid / metabolism*
Protein-Arginine N-Methyltransferases / genetics*
Protein-Arginine N-Methyltransferases / metabolism
RNA, Small Interfering
Real-Time Polymerase Chain Reaction
Tumor Suppressor Proteins / genetics*
Tumor Suppressor Proteins / metabolism

Substances

Btg2 protein, mouse
Ccnd3 protein, mouse
Cyclin D3
DNA-Binding Proteins
Homeodomain Proteins
Immediate-Early Proteins
Immunoglobulin Light Chains
RNA, Small Interfering
Rag2 protein, mouse
Tumor Suppressor Proteins
RAG-1 protein
Prmt1 protein, mouse
Protein-Arginine N-Methyltransferases
Cdk4 protein, mouse
Cyclin-Dependent Kinase 4