P-258: LGR4 promotes plasma cell malignancy and myeloma cell homing by activating NF-κB signaling pathway

Introduction: Multiple myeloma (MM) is a plasma cell malignancy characterized by clonal proliferation in the bone marrow. The mechanism of cell homing and migration which critical for myeloma tumorigenesis and progression. As the fourth member of the G protein-coupled receptors (GPCRs), LGR4 is involved in a variety of physiological and pathological processes. Study shows LGR4 is involved in early haematopoietic fractionation, while high expression of LGR4 is associated with poor prognosis in variety of cancer. LGR4 can promote breast cancer bone metastasis and it is highly expressed in MM patients. However, the unique function and mechanism of LGR4 in plasma cell malignancy and in MM remined unclear.

Methods: LGR4 conditional knockout mice confirmed LGR4 deletion inhibits plasma cell differentiation. Gene editing technology and adoptive B cell transplantation mouse model to verify the malignant transformation effect of LGR4. Overexpression and knockdown of LGR4 in MM cell line verified the function and mechanism in MM both in vivo and in vitro.

Results: Firstly, In vitro induced plasma cell differentiation results show interference with LGR4 expression inhibited B cell proliferation and plasma cell differentiation by used LGR4 conditional knockout mice and Cas9 tag mice. Interestingly, the adoptive B cell transplantation by VκMYC mice confirmed that over expression of LGR4 promotes B cell malignant transformation and bone destruction. Taken together, our earlier findings suggested LGR4 promotes plasma cell malignant transformation.

Simultaneously, to identify the unique function and mechanism of LGR4 in myeloma, we have determined high-expression of LGR4 is associated with cell adhesion in MM and linked to poor prognosis. Overexpression of LGR4 promotes cell adhesion, migration and homing in MM cells, while knockdown of LGR4 suppresses both in vitro and in vivo. Mechanistically, we established that high expression of LGR4 in MM cells activated NF-κB signaling pathway and promoted the expression of migration-related adhesion molecule, thus accelerated the MM cell homing and tumor progression both in vitro and in vivo.

Conclusions: In conclusion, evidence from our study show that LGR4 promotes plasma cell malignancy transformation both in vivo and in vitro. Meanwhile, our results show LGR4 in MM cells contribute to MM progression by modulating cell-adhesion to promote MM cell homing to BM. LGR4 activates NF-κB signaling which facilitates cell homing and the inhibition of NF-κB signaling pathway in MM. Taken together, our findings highlight the mechanistic role of LGR4 in plasma cell malignancy transformation and MM cell homing, revealed a therapeutic strategy for MM by targeting LGR4.