RHOA Controls Oncogenic B-Cell Receptor Signaling in Aggressive Lymphoma

Diffuse large B cell lymphoma (DLBCL), divided into activated B-cell-like (ABC) and germinal center B-cell-like (GCB), is the most common type of aggressive lymphoma. While many studies have shown treatment response differences based on subtype, recurrently mutated proteins can further alter these responses and may require therapeutic alterations. Mutational effects in DLBCL have recently begun to be investigated, of which one mutated protein, the master cytoskeletal regulator RhoA, is here evaluated. While having been identified in previous studies, a complete investigation into the effects of this protein and its mutations in the context of DLBCL have been lacking. Through use of various methodologies, RhoA was found to play a role in the chronic active BCR signaling and NF-?B survival signal that are characteristic for the ABC DLBCL subtype. Not only was it essential in proximal BCR signaling, but additionally in the formation of the My-T-BCR super-signaling complex. Additionally, the interaction with essential surface membrane signalling proteins, and effects on internalization, emphasize the importance of this protein. Differing point mutations alter the activity of RhoA itself, along with its response to various clinically relevant inhibitors, clustering of IgM on the plasma membrane, and the actin cytoskeleton. The investigation of RhoA and its recurrent mutations are essential for deeper understanding of this malignancy. Overall design: RNA-seq profiling of ABC DLBCL cell lines after 10hr of DMSO, Rhosin, or Ibrutinib treatment. RNA-seq profiling of TMD8 RhoA WT cells and TMD8 p.R5W cells under Copanlisib treatment.