B-cell receptor (BCR) is a B cell hallmark surface complex regulating multiple cellular processes in normal as well as malignant B cells. Igα (CD79a)/Igβ (CD79b) are essential components of BCR that are indispensable for its functionality, signal initiation, and signal transduction. CD79a/CD79b-mediated BCR signaling is required for the survival of normal as well as malignant B cells via a wide signaling network. Recent studies identified the great complexity of this signaling network and revealed the emerging role of CD79a/CD79b in signal integration. In this review, we have focused on functional features of CD79a/CD79b, summarized signaling consequences of CD79a/CD79b post-translational modifications, and highlighted specifics of CD79a/CD79b interactions within BCR and related signaling cascades. We have reviewed the complex role of CD79a/CD79b in multiple aspects of normal B cell biology and how is the normal BCR signaling affected by lymphoid neoplasms associated CD79A/CD79B mutations. We have also summarized important unresolved questions and highlighted issues that remain to be explored for better understanding of CD79a/CD79b-mediated signal transduction and the eventual identification of additional therapeutically targetable BCR signaling vulnerabilities.

Key Points: The GCB subtype of DLBCL relies exclusively on tonic BCR signaling via CD79A Y188. PTEN protein expression and BCR surface density determine the contribution of tonic BCR signaling to AKT activity in GCB-DLBCL.

Purpose: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphomas characterized by (over)expression of BCL2. A BCL2-targeting drug venetoclax (VTX) has promising anticancer activity in MCL. We analyzed molecular mechanisms of VTX resistance in MCL cells, and tested strategies to overcome it. Experimental Design: We confirmed key roles of proapoptotic proteins BIM and NOXA in mediating VTX-induced cell death in MCL. Both BIM and NOXA are, however, differentially expressed in cell lines compared to primary cells. First, NOXA protein is significantly overexpressed in most MCL cell lines. Second, deletions of BIM gene harbored by three commonly used MCL cell lines (JEKO-1, MINO and Z138) were not found by array comparative genomic hybridization using a validation set of 24 primary MCL samples. Results: We demonstrated that MCL1 and NOXA play important roles in mediating resistance to VTX. Consequently, we tested an experimental treatment strategy based on co-targeting BCL2 with VTX and MCL1 with a highly specific small molecule MCL1 inhibitor S63845. The combination of VTX and S63845 demonstrated synthetic lethality in vivo on a panel of five patient-derived xenografts established from patients with relapsed MCL with adverse cytogenetics. Conclusions: Our data strongly support investigation of VTX in combination with S63845 as an innovative treatment strategy for chemoresistant MCL patients with adverse cytogenetics in the clinical grounds.

Histone methylation and demethylation regulates B-cell development, and their deregulation correlates with tumor chemoresistance in diffuse large B-cell lymphoma, limiting curative rates. Since histone methylation status correlates with disease aggressiveness and relapse, we investigated the therapeutic potential of inhibiting histone 3 Lys27 demethylase KDM6B, in-vitro, using the small molecule inhibitor GSK-J4. KDM6B is overexpressed in the DLBCL germinal center B-cell subtype, and higher KDM6B levels are associated with worse survival in DLBCL patients treated with R-CHOP. GSK-J4 induced apoptosis was observed in five (SU-DHL-6, OCI-Ly1, Toledo, OCI-Ly8, SU-DHL-8) out of nine GCB-DLBCL cell lines. Treatment with GSK-J4 predominantly resulted in downregulation of BCR signaling and Bcl6. Cell lines expressing high Bcl6 levels or CREBBP/EP300 mutations were sensitive to GSK-J4. Our results suggest that BCR dependent downregulation of Bcl6 is responsible for GSK-J4-induced cytotoxicity. Further, GSK-J4 mediated inhibition of KDM6B sensitizes GCB-DLBCL cells to chemotherapy agents that are currently utilized in DLBCL treatment regimens.