Efficacy of bispecific antibodies in the treatment of extramedullary disease and high risk cytogenetics in relapsed multiple myeloma: a systematic review

CLINICAL LYMPHOMA MYELOMA & LEUKEMIA(2023)

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摘要
Our previous study identified that CRIP1 was a high-risk gene that overexpressed in drug-resistance MM cells in post-treatment patient samples.However, the molecular mechanism of CRIP1 in myelomagenesis has not been fully understood.In this study, we evaluated the mechanism of CRIP1-mediated PIs resistance and MM cell aggressive proliferation.Methods: An inducible CRIP1-shRNA vector and CRIP1 overexpress vector were constructed to explore the role of CRIP1 in MM.Co-IP(Co-Immunoprecipitation) with TAP/MS (Tandem affinity purification/Mass spectrum) was performed to detect the binding of USP7, CRIP1 and PA200.Myeloma xenograft model was used to determine the role of CRIP1 to promote proliferation of MM cells and induce BTZ resistance in vivo.Results: Our data showed that CRIP1 was overexpressed in MM cells especially in patients with RRMM (relapsed/refractory MM).CRIP1 overexpression is linked to inferior outcome in patients with MM even those undergoing bortezomib (BTZ) treatment.CRIP1 promoted MM cell proliferation, invasion and decreased PIs sensitivity in MM cells.More important, CRIP1 overexpression stabilized PA200 and against PIs induced MM cell apoptosis by enhancing the proteasome activity and autophagy.Co-IP and TAPMS analysis indicated that CRIP1 promoted the deubiquitination and stabilization of PA200 by binding with USP7.Strikingly, our study elucidated for the first time that CRIP1 and PA200 were both the substrates of USP7.CRIP1 worked as a scaffold protein and played critical roles in BTZ resistance by forming the complex with USP7 and PA200.In vitro and in vivo studies further confirmed that the USP7 or PSME4 inhibition reduces CRIP1 induced BTZ -resistance in MM.Conclusions: In summary, CRIP1 was overexpressed in MM cells and correlated with inferior outcome of MM patients.CRIP1 induced drug resistance to proteasome inhibitors by promoting proteasome activity and autophagy in MM.CRIP1 promoted PA200 bound with USP7 through facilitating proteasome activity and autophagy and induced the BTZ resistance of MM cells.Blocking CRIP1/USP7/PA200 signal pathway would be an ideal strategy for MM therapy which can suppress proteasome activity and autophagy simultaneously.
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关键词
multiple myeloma,extramedullary disease,bispecific,high risk cytogenetics
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