LAUSR

Unique molecular vulnerabilities have been identified in the aggressive MCD/C5 genetic subclass of diffuse large B cell lymphoma (DLBCL). However, the pre-malignant cell-of-origin exhibiting MCD-like dependencies remains elusive. In this study, we examined animals carrying up to four hallmark genetic lesions found in MCD consisting of gain-of-function mutations in Myd88 and Cd79b, loss of Prdm1 and overexpression of BCL2. We discovered that expression of combinations of these alleles in vivopromoted a cell-intrinsic accumulation of B cells in spontaneous splenic germinal centers (GCs). Like MCD, these pre-malignant B cells were enriched for B-cell receptors (BCRs) with evidence of self-reactivity, showed a de novo dependence on Tlr9 and were more sensitive to inhibition of BTK. Mutant spontaneous splenic GC B cells (GCB) showed increased proliferation and IRF4 expression. Mice carrying all four genetic lesions showed a greater than 50-fold expansion of spontaneous splenic GCs exhibiting aberrant histologic features with a dark zone immunophenotype and went on to develop DLBCL in the spleen with age. Thus, by combining multiple hallmark genetic alterations associated with MCD, our study identifies aberrant spontaneous splenic GCB as a likely cell-of-origin for this aggressive genetic subtype of lymphoma.