The G-Protein Coupled Receptors and G-Proteins Alpha Expression in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a B cell Non-Hodgkin lymphoma comprising approximately 8% of malignant lymphomas. MCL is considered to be an incurable disease even though survival has improved with novel biological therapies that interrupt survival signaling from the lymphoma microenvironment. The signaling pathways that are deregulated and the factors leading to systemic dissemination of the disease are still poorly understood. There is also a clear need to identify additional druggable targets for therapy (Saba and Wiestner, Curr Opin Hematol, 2014). Druggable targets may be G-protein coupled receptors (GPCRs) and G-proteins. GPCRs belong to the family of seven transmembrane receptors, which upon activation by extracellular ligands transfer the signals inside the cell for activation of the specific pathway. The signaling involves G-proteins. G-proteins consist of the subunits: alpha, beta and gamma and their subtypes. During GPCR activation the G alpha subunit is released and the subtype of G-protein subunit determines which downstream signaling pathways (including Akt, PI3K, ERK, JNK, MAPK, NFkappaB and others) is then activated. In the immune cells different subtypes of G-proteins alpha are instrumental for leukocyte migration, architecture of B cells compartments in spleen, thymus, lymph nodes, and gastrointestinal tract (Hwang et al., PlosOne, 2013) and BCR-mediated cell death (Misra et al., J Exp Med, 2010). G alpha13 signaling is involved in development of germinal centre-derived lymphomas (Muppidi et al., Nature, 2014).

In order to map the aberrant expression of GPCR and G-proteins in MCL, the expression of genes encoding for GPCRs and G-protein alpha subunits was analyzed by Affymetrix U133A Array of seventeen MCL biopsies and eight non-malignant lymph nodes. Among investigated GPCR and G-protein alpha subunit genes 25/298 were differently expressed in MCL compared to reactive lymph nodes (moderated t-test, adj. p=or< than 0.05). The four most significantly different genes expressed were: LPAR6, GPRC5C, OPN3 and GNAZ (all adj.p<0.003). The latter, GNAZ, encodes for G-protein alpha z. The analysis of GNAZ by qPCR in 77 additional MCL biopsies from a population-based Stockholm MCL cohort showed varied expression of GNAZ. Interestingly, the MCL cases, which expressed the highest levels of GNAZ, had significantly worse survival (Kaplan-Meier, log rank, p<0.003) suggesting that GNAZ has, a yet unknown, role in MCL biology. Further analysis showed that GNAZ expression was correlated to lymphocytosis (Mann-Whitney test, p=0.023) and leukocytosis (Mann-Whitney test, p=0.011) in MCL patients but not to: high tumor cell proliferation, blastoid morphology nor to p53 immunoreactivity. Our results suggest that GNAZ-signaling is of importance for cell-cell interaction in the tumor microenvironment and/or for egress of lymphoma cells to the blood.