GPR34 translocation and mutation are linked to MALT lymphoma of the salivary gland (SG-MALT-lymphoma). The majority of GPR34 mutations occur at the C-terminus, resulting in shortened proteins that lack the critical phosphorylation motif for receptor desensitization. It was unknown why GPR34 mutations were linked to SG-MALT lymphoma and how these mutations contribute to lymphoma formation. For a study, researchers created isogenic Flp-InTRex293 cell lines that expressed a single copy of GPR34 or its mutations and carried out a variety of in vitro tests. They discovered that the GPR34 Q340X truncation provided considerably enhanced resistance to apoptosis and more transforming capacity than the GPR34 wild type, but not the R84H & D151A mutants. After ligand (lysophosphatidylserine) activation, the GPR34 truncation mutant displayed considerably delayed internalization relative to the wild type. The GPR34 Q340X truncation, and to a lesser extent the D151A mutant, notably stimulated CRE, NF-B, and AP1 reporter activities, especially in the presence of ligand stimulation, among the 9 signaling pathways studied. The increased activities of phospholipase-A1/2 in the culture supernatant of Flp-InTRex293 cells expressing the GPR34 Q340X mutant, as well as their ability to catalyze the formation of lysophosphatidylserine from phosphatidylserine, were also characterized.
Importantly, phospholipase-A1 was found in high amounts in the duct epithelium of salivary glands and lymphoepithelial lesions (LELs). The findings supported a concept of GPR34-mediated paracrine activation of malignant B cells in which LELs release phospholipase A, which hydrolyzes the phosphatidylserine exposed on apoptotic cells to produce lysophosphatidylserine, the ligand for GPR34.