CRIP1 INDUCES PIS RESISTANCE BY FORMING A COMPLEX WITH USP7 /PA200 AND ENHANCING PROTEASOME ACTIVITY AND AUTOPHAGY IN MULTIPLE MYELOMA

Introduction: Multiple myeloma (MM) is a plasma malignancy characterized by an accumulation of misfolded immunoglobulins in the cell. Although proteasome inhibitor (PI) can treat MM inhibiting ubiquitin-proteasome system (UPS), autophagy as compensatory protein clearance mechanism, it still leads to drug resistance. The discovery new targets that simultaneously inhibit UPS and will provide great potential for treatment MM. Methods: proliferation, invasion, migration, activity were detected CRIP1- knockdown /overexpression control cells. Co-IP (Co-Immunoprecipitation) with TAP/MS (Tandem affinity purification/Mass spectrum) was performed detect binding USP7, CRIP1 PA200. Myeloma xenograft model used determine role promote proliferation cells induce BTZ resistance vivo. Results: levels significantly increased from NDMM (newly diagnosed multiple myeloma) compared healthy donors, further patients RRMM (relapsed/refractory myeloma). Moreover, high expression significantly related poor prognosis patients, especially those treated BTZ. Our results vitro vivo showed noteworthy inhibited cell growth, migration. more sensitive PIs-induced growth arrest when knockdown. level LC3B-Ⅱ reduced analysis formed complex USP7/PA200. decreased ubiquitination USP7 inhibition. These data suggested substrate USP7.CRIP1 promotes de-ubiquitination stabilization PA200 mediated interacting PA200, which turn survival resistant. Functional inhibition knocking down or PSME4 OE line led decrease autophagy, thus enhancing sensitivity PIs intro Conclusion: plays critical progression formation CRIP1/USP7/PA200 complex. High biomarker high-risk patients. target therapy, autophagy. Encore Abstract - previously submitted EHA 2023 research funded following foundations:(a) CAMS Innovation Fund Medical Sciences (CIFMS) (2021-I2M-1-040 2022-I2M-1-022), (b) National NaturalScience Foundation China (82170194, 81920108006, 82270175) Natural Science Fujian Province (2021J02040). Keywords: Diagnostic Prognostic Biomarkers, Myeloma, Tumor Biology Heterogeneity No conflicts interests pertinent abstract.