Biology subjects

Youssfi, A. A.

Publications and source records attributed to Youssfi, A. A..

3 recordsLinked to original sources

bioRxiv2026

BCL10 Gain-of-Function Impairs Germinal Center Participation by Naive B Cells and Cooperates with BCL6 to Drive Extrafollicular Diffuse Large B-Cell Lymphoma

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 naive 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.

cancer biology↗

bioRxiv2026

Lymphoma response to chimeric antigen receptor T cell therapy is driven by endogenous tumor-reactive CD8⁺ T cells

CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy induces durable remissions in a subset of patients with relapsed or refractory large B-cell lymphoma; however, most patients fail to respond or eventually relapse. By integrating whole-genome and transcriptome profiling of 54 patients with functional assays, syngeneic models, and mathematical modeling, we demonstrate that durable CAR-T efficacy requires cooperation between CAR-T cells and endogenous CD8 (eCD8) T cells recruited to join the attack on malignant cells. Tumors with biallelic loss of MHC class I or CD58 exhibited high genomic complexity, increased neoantigen burden, and resistance to CAR-T therapy. MHC-I-deficient lymphomas showed suboptimal response in immunocompetent hosts compared to wild type. Importantly, sustained responses in mice occurred only in the presence of eCD8 cells, whereas all CD8-depleted mice relapsed after initial CAR-T-mediated tumor regression. Patients and murine ELISPOT assays confirmed enhanced endogenous T-cell activation post-CAR-T. These findings reveal that CAR-T therapy functions not only as a cytotoxic modality but also as a catalyst for endogenous anti-tumor immunity.

cancer biology↗

bioRxiv2025

RHOA Loss of Function Impairs the IFNγ Response and Promotes CD19 Antigen Escape to Drive CAR-T Resistance in Diffuse Large B-cell Lymphoma

CD19-directed chimeric antigen receptor (CAR)-T cells are breakthrough therapies for aggressive B-cell lymphomas, but less than half of patients achieve durable responses. We previously showed through whole-genome sequencing of tumors from CAR-T-treated patients that deletions of RHOA (3p21.31) are enriched in cases progressing after treatment. RHOAs roles in resistance and pathogenesis are poorly defined, despite loss-of-function alterations that occur in [~]20% of newly diagnosed large B-cell lymphoma (LBCL) cases. We created RHOA-deficient LBCL systems and confirmed cell-intrinsic loss of response to CAR-19 in vitro and in vivo driven by CD19 downregulation. Impact on CD19, however, was variable and would not explain selection for RHOA deletion in newly diagnosed cases. We therefore created RHOA-deficient tumors in immunocompetent mice and found remarkable correlation with dysfunctional lymphoma microenvironment (LME) signatures in CAR-19 resistant patients. These LMEs are marked by a type 1-like immune infiltrate with terminally exhausted CD8 T cells, Th1-like CD4 cytotoxic lymphocytes (CTLs), and increased production of interferon gamma (IFN{gamma}). RHOA-deficient tumor cells themselves have significantly impaired IFN{gamma} responses, providing resistance to CD8 T cell clearance by way of diminished induction of major histocompatibility complex class I (MHC-I). These findings support a model that depletion of healthy effector populations by RHOA-deficient lymphoma is a key driver of immune dysfunction thwarting CAR-19 clinical responses. Overall, we describe for the first time how a single-gene alteration found recurrently in CAR-19-resistant LBCL contributes to treatment failures.

cancer biology↗