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• W4385951684 abstract "Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: MARCH5 (Membrane Associated Ring-CH-Type Finger 5, also known as MITOL) is an E3 ubiquitin ligase localized on the outer membrane of mitochondria which plays a crucial role in controlling mitochondrial dynamics. A close link between disturbed mitochondrial dynamics and cancers has been demonstrated. Also, MARCH5 RNA may act as a competing endogenous RNA in the expression regulation of SMAD2 and ATG5, leading to an enhanced autophagic activity. MARCH5 is indicated to be an essential gene in different multiple myeloma (MM) cell lines which produce aberrant immunoglobulin. Therefore, we hypothesize that it may play an oncogenic role in MM malignancy. Aims: To elucidate the biological functions and clinical significance of MARCH5 in MM and the underlying mechanisms. Methods: The effects of MARCH5 depletion on cell biology were determined through lentiviral knockdown of MARCH5 in several MM cell lines including KMS11, KMS18, RPMI8226 and MM.1s, and subsequent in vitro assays such as cell viability, growth, and apoptosis analysis. The mechanisms behind MARCH5 regulation of MM cell viability and apoptosis were evaluated by qPCR, Western blot (WB), Cyto ID staining and RNA sequencing techniques. In addition, clinical importance of MARCH5 was explored in various datasets including HOVON and CoMMpass datasets as well as Italian and Singaporean (CWJ) groups. Results: Cell viability and cell growth of MM cell lines were significantly decreased associated with a significant increase in apoptosis upon MARCH5 depletion, mainly due to the reduced autophagic activity, as demonstrated by a downregulation of LC3I/II along with BECLIN1, the key proteins in the autophagosome initiation and formation. Consistent to WB and RNA seq results, Cyto ID staining analysis showed a reduced autophagosome formation in knockdown groups vs Scramble, further confirming the reduced autophagic activity. Furthermore, a downregulation of IRE1 and XBP1s, mediators of signals enhancing protein folding and degradation of un-/mis-folded proteins, was observed which might explain the aggravated compromised cell survival. Moreover, patient sample-derived RNA-seq and tissue microarray data analysis revealed that MARCH5 expression was progressively increased during the course of MM malignancy and has a strong correlation with overall survival (OS) and progression free survival (PFS), indicating a possible oncogenic role of MARCH5 in MM disease formation and progression. Summary/Conclusion: Collectively, our findings indicate that MARCH5 may play a crucial oncogenic role in MM cells. Regarding the clinical data base, MARCH5 correlation with MM disease progression as well as OS and PFS may provide evidence on the therapeutic targeting of MARCH5 for MM therapy. Keywords: Multiple myeloma" @default.
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• W4385951684 date "2023-08-01" @default.
• W4385951684 modified "2023-10-17" @default.
• W4385951684 title "P833: MARCH5 AS A POTENTIAL THERAPEUTIC TARGET IN MULTIPLE MYELOMA" @default.
• W4385951684 doi "https://doi.org/10.1097/01.hs9.0000970236.23384.06" @default.
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