Journal Article

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

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

2017

Overview

Expression of a competent Igh heavy chain initiates a pre-BCR checkpoint during B cell development. Reth and colleagues show that protein arginine methylation by a BTG2-PRMT1 complex is required to inactivate CDK4 and thereby establish pre-B cell arrest. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13 / 13/1 / 13/109 / 13/31 / 13/95 / 38 / 38/1 / 38/22 / 38/70 / 38/77 / 38/88 / 631/250/232/2058 / 64/60 / 692/699/67/1990/283 / 82/58 / 82/80 / 96 / Animals / Arginine / B cells / BCR-ABL protein / Biomedicine / Bone marrow / BTG2 protein / Cell cycle / Cell Cycle Checkpoints / Cell differentiation / Cell Differentiation - genetics / Cell proliferation / Cell Proliferation - genetics / Cyclin D3 - metabolism / Cyclin-dependent kinase 4 / Cyclin-Dependent Kinase 4 - metabolism / Cyclin-dependent kinases / Development and progression / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Flow Cytometry / Gene Knockdown Techniques / Gene Rearrangement, B-Lymphocyte - genetics / Genes, abl - genetics / Genetic aspects / Health aspects / Homeodomain Proteins - genetics / Homeodomain Proteins - metabolism / Immediate-Early Proteins - genetics / Immediate-Early Proteins - metabolism / Immunoglobulin Light Chains - genetics / Immunology / Infectious Diseases / Kinases / Leukemia / Leukemogenesis / Lymphocytes B / Lymphopoiesis - genetics / Mass Spectrometry / Methyltransferases / Mice / Precursor Cells, B-Lymphoid - cytology / Precursor Cells, B-Lymphoid - metabolism / Protein-Arginine N-Methyltransferases - genetics / Protein-Arginine N-Methyltransferases - metabolism / RAG1 protein / RAG2 protein / Real-Time Polymerase Chain Reaction / RNA, Small Interfering / Translocation / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - metabolism