The class-specific BCR tonic signal modulates lymphomagenesis in a c-myc deregulation transgenic model.

Rada Amin,Karin Tarte,Christelle Oblet,Aurélie Chanut,Michel Cogné,Yves Denizot,Abdelghafour Marfak,Céline Pangault

doi:10.18632/oncotarget.2297

Abstract

Deregulation of c-myc by translocation onto immunoglobulin (Ig) loci can promote B cell malignant proliferations with phenotypes as diverse as acute lymphoid leukemia, Burkitt lymphoma, diffuse large B cell lymphoma, myeloma... The B cell receptor (BCR) normally providing tonic signals for cell survival and mitogenic responses to antigens, can also contribute to lymphomagenesis upon sustained ligand binding or activating mutations. BCR signaling varies among cell compartments and BCR classes. For unknown reasons, some malignancies associate with expression of either IgM or class-switched Ig. We explored whether an IgA BCR, with strong tonic signaling, would affect lymphomagenesis in c-myc IgH 3'RR transgenic mice prone to lymphoproliferations. Breeding c-myc transgenics in a background where IgM expression was replaced with IgA delayed lymphomagenesis. By comparison to single c-myc transgenics, lymphomas from double mutant animals were more differentiated and less aggressive, with an altered transcriptional program. Larger tumor cells more often expressed CD43 and CD138, which culminated in a plasma cell phenotype in 10% of cases. BCR class-specific signals thus appear to modulate lymphomagenesis and may partly explain the observed association of specific Ig classes with human B cell malignancies of differential phenotype, progression and prognosis.

Highlights

In normal cells, c-myc oncogene expression is restricted to the early G1 phase of the cell cycle with a role in proliferation, differentiation, metabolism and apoptosis [1]
Deregulation of the c-myc gene is a constant feature of human Burkitt lymphoma (BL), with translocations linking c-myc to any of the immunoglobulin heavy or light chain (IgH, Igκ or Igλ) locus and with a phenotype that may vary from immature RAG expressing B cell lymphoma or leukemia to mature B cell lymphoma [2]
Numbers of B cells did not differ between homozygous α1KI mice and the double transgenic α1KI c-myc3’RR, neither in spleen (6.7 ± 1.7% N=5 for α1KI versus 8.9 ± 2.1% N=5, i.e. 1.4 ± 0.4 106 cells vs 1.3 ± 0.19 106 cells), nor in lymph nodes (LNs) (5.1 ± 0.8%, n=3 vs 5.3 ± 1.2%, n=3, i.e. 0.62 ± 0.09 106 cells vs 0.44 ± 0.14 106 cells)

Summary

Introduction

C-myc oncogene expression is restricted to the early G1 phase of the cell cycle with a role in proliferation, differentiation, metabolism and apoptosis [1]. Translocation onto the IgH locus is frequent in human myeloma and mouse plasmacytoma cases, suggesting that c-myc may participate to cell transformation at all stages of B cell differentiation. Beside oncogenes and the role of signals from the microenvironment, the phenotype of B cell malignancies often involves signaling through the adaptive or innate immune receptors. The B cell receptor (BCR) is mandatory for survival of normal B cells by providing a ligand-independent tonic signal. It is the main receptor controlling B cell activation during immune responses [5]. Expression of Ig of the various classes has a clear influence on normal B cell fate [6,7,8,9]

Methods

Results

Conclusion