Venu Venkatarame Gowda Saralamma

BCL10 gain-of-function (GoF) mutations occur in diffuse large B-cell lymphoma (DLBCL) cases of the BN2/C1 molecular subgroup. These alterations activate CARD11-BCL10-MALT1 (CBM) signaling and drive resistance to multiple drug classes, but their role in disease pathogenesis is incompletely understood. In particular, interactions between BCL10 GoF and additional DLBCL oncogenes are undefined. Here, we show BCL10 GoF in naïve B cells blocks their participation in germinal center (GC) reactions and permits transformation to DLBCL with a non-GC B-cell phenotype. Most clinical cases with BCL10 GoF also carry translocation of the BCL6 proto-oncogene, and we show that co-activation of these two lesions together promotes pronounced oncogenic synergy. Detailed single-cell analyses of underlying premalignant B-cell populations revealed expansion of extrafollicular memory B cells whose gene-expression program remains prominent in resulting lymphomas in both the mouse and corresponding human tumors. We therefore define a novel role for BCL10 activating mutations in enabling BCL6 lymphomagenesis. Statement of Significance: Complex mutational patterns underlie molecular subtypes of DLBCL, the most common lymphoma. We define the basis for synergy between co-deregulated oncogenes in a disease cluster commonly arising from non-GC B-cells. Extrafollicular memory B cells are implicated as the precursors undergoing malignant transformation by the dual deregulation of BCL6 and BCL10 .

Genomic features associated with CAR-19 progression.

Phenotypic characterization of RHOA LoF lymphoma cell lines.

CD19 loss is RHOA-dependent and regulated at the mRNA level.

Pathway analysis and LME features of syngeneic shRhoa tumors.

Characteristics of tumor and CAR-T cells in scRNA-seq data of CAR-T treated mice.

IFNγ-induced cytokine secretion and viability of parental and RHOA LoF lymphoma systems.

Supplementary Table 1 from RHOA Deletion Downregulates CD19 and Promotes Dysfunctional Immune Microenvironments in CAR T–Resistant Large B-cell Lymphomas

Patient characteristics in the combined data sets.

RNA-seq of RIVA sgRHOA engineered cells.