MyD88 and Cxcr4 gain-of-function mutations lead to ABC accumulation in a “Waldenstrom-like” model in mice
KHAMYATH M. 1,2, BONAUD A. 1,2, ROLAND L. 1,2, MELHEM H. 1,2, LAZENNEC G. 3, DULPHY N. 1,2, FEUILLARD J. 4, VINCENT-FABERT C. 4, BALABANIAN K. 1,2, ESPÉLI M. 1,2
1 Université Paris-Cité, Institut de Recherche Saint-Louis, INSERM U1160, Paris, France; 2 OPALE Carnot Institute, The Organization for Partnerships in Leukemia, Hôpital Saint-Louis, Paris, France; 3 CNRS, SYS2DIAG-ALCEDIAG, Cap Delta, Montpellier, France; 4 UMR CNRS 7276/INSERM U1262 CRIBL, University of Limoges, and Hematology Laboratory of Dupuytren Hospital University Center (CHU) of Limoges, Limoges, France
Objectives : Waldenström Macroglobulinemia (WM) is a B lymphoplasmacytic lymphoma characterized by bone marrow (BM) infiltration of clonal IgM+ cells with a phenotype ranging from activated B cells to plasma cells (PCs). MYD88 gain of function mutations are found in 90% of cases and are associated in 30% of cases with a gain-of-function mutation of CXCR4. Patients with both mutations have higher BM infiltration and IgM titres. MYD88 is implicated in the signalling pathway downstream of Toll-like receptors (TLR) while CXCR4 is a chemokine receptor involved in different cellular processes including cell migration, proliferation, and differentiation. Despite progresses made in the last few years, how both mutations synergize to promote a more invasive disease is still unclear.
Methods : To better understand how MyD88 and Cxcr4 signalling may synergize to promote WM, we crossed mice bearing both gain of function mutations and compared WT mice to single and double mutant mice. We used those mice to characterize B cell subsets and study how MyD88 and Cxcr4 mutations impact their capacity to differentiate into PC.
Results : The double mutant mice displayed enhanced splenomegaly associated with a reduced lifespan compared to all control groups. Moreover, they also had higher serum IgM and higher number of IgM-secreting cells in the BM and spleen. The double mutant mice displayed an increase of splenic Age associated B cells (ABC), a B cell population that accumulates with age. RNASeq analysis highlights defects of their metabolism and this observation was confirmed by functional assays.
Conclusion : Altogether, by comparing these different mouse models we demonstrated that over-activated MyD88 and Cxcr4 signalling pathways synergize to promote a deleterious hyper-IgM syndrome associated with an increase of ABC, that could be responsible for a dysregulation of B and PC homeostasis.