WAVE2 and Tpm3.1/3.2 : actin dynamics, B-cell biology, and targeting B-cell lymphomas

Abstract

Activation of the B cell requires dynamic remodeling of the actin cytoskeleton upon interaction with antigen-presenting cells. This enables cell spreading on antigen-bearing surfaces, immune synapse formation, and sustained B-cell receptor signaling. A central regulator of these events is the Arp2/3 complex, which drives the formation of branched actin networks in response to antigen stimulation. Of the nucleation-promoting factors that activate the Arp2/3 complex, the roles of WASp and N-WASp in B cells have been well-studied, but the contribution of WAVE2 has not been investigated. My work showed that WAVE2 and the Arp2/3 complex colocalize at the peripheral F-actin ring formed during B cell spreading. siRNA-mediated knockdown of WAVE2 led to impaired and delayed B cell spreading, reduced actin retrograde flow, and disrupted formation of actomyosin arcs. These defects diminished BCR signaling at the immune synapse and impaired B cell activation in response to antigen-presenting cells. In parallel, I investigated the role of tropomyosin isoforms Tpm3.1 and Tpm3.2, which stabilize actin filaments and regulate the recruitment of myosin. Tropomyosin function in B cells had not been studied previously. Using ATM-3507, a selective small-molecule inhibitor of Tpm3.1/3.2, I showed that disrupting Tpm3.1/3.2 function severely impaired BCR-induced actin remodeling, cell spreading, and actomyosin arc assembly, consistent with its localization at the cell periphery and actin arcs. Moreover, treating diffuse large B-cell lymphoma cells with ATM-3507 inhibited their growth, induced G2/M arrest, and reduced CXCL12-induced chemotaxis and motility on fibronectin. Collectively, these findings highlight WAVE2 and Tpm3.1/3.2 as key regulators of B cell actin architecture and B cell function, while positioning Tpm3.1/3.2 as a promising therapeutic target for B cell malignancies such as DLBCL.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat