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Analysis for expression of genes in multiple myeloma cells treated with PRIMA-1Met or dimethyl sulfoxide (DMSO) control

ABSTRACT: Targeting p53 by the small molecule PRIMA-1Met/APR-246 has shown promising preclinical activity in various cancer types. However, the mechanism of PRIMA-1Met-induced apoptosis is not completely understood and its effect on multiple myeloma (MM) cells is unknown. In this study we evaluated anti-tumor effect of PRIMA-1Met alone or combined with current anti-myeloma agents in MM cell lines, patient samples, and a mouse xenograft model. Results of our study showed that PRIMA-1Met decreased the viability of MM cells irrespective of p53 status with limited cytotoxicity toward normal hematopoietic cells. PRIMA-1Met restored wild type conformation of mutant p53 and induced activation of p73 up-regulating Noxa and down-regulating Mcl-1 without significant modulation of p53 level. Importantly, PRIMA-1Met delayed tumor growth and prolonged survival of mice bearing MM tumor. To identify the potential targets of PRIMA-1Met, we performed gene expression profiling (GEP) by microarray in three different cell lines harboring wild type, mutant or null p53 and analysed differential expression of target genes between PRIMA-1Met treated and non-treated samples. Based on our we conclude that treatment of MM cells with PRIMA-1Met lead to induction of p73-mediated apoptosis by up-regulating Noxa and down-regulating Mcl-1 irrespective of p53 status.

ORGANISM(S): Homo sapiens

PROVIDER: GSE46609 | GEO | 2013/05/04

SECONDARY ACCESSION(S): PRJNA201122

REPOSITORIES: GEO

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Project description:Amyloid light chain amyloidosis (AL) is an incurable protein misfolding disorder characterized by the production of amyloidogenic immunoglobulin light chains by clonal populations of plasma cells. These abnormal light chains accumulate as amyloid fibrils in vital organs and cause multi-organ dysfunction that can be rapidly fatal. Current treatment regimens, which include proteasome inhibitors, were developed for the treatment of the more common plasma cell disease multiple myeloma and have demonstrated efficacy in AL amyloidosis. However, use of these agents is frequently limited due to multi-organ dysfunction at presentation, resulting in a median survival of 2-3 years and underscoring the need for novel therapies. By analyzing bone marrow-derived plasma cells from 44 patients with AL amyloidosis, we find that clonal plasma cells are highly primed to undergo apoptosis and exhibit strong dependencies on pro-survival BCL-2 family proteins that can potentially be targeted by recently-developed BH3 mimetics. In particular, we find that clonal plasma cells are highly dependent on the pro-survival MCL-1 and undergo apoptosis in response to single-agent treatment with an MCL-1 inhibitor. Notably, this MCL-1 dependency is indirectly targeted by the proteasome inhibitor bortezomib, which is currently the standard of care for this disease, via the stabilization of Noxa and its direct inhibitory binding to MCL-1. BCL-2 inhibition with the FDA-approved inhibitor venetoclax (ABT-199) sensitizes plasma cells to bortezomib treatment and other front-line therapies, which can be observed in vitro and in vivo. Mass spectrometry-based proteomic analysis reveals changes in signaling pathways regulating apoptosis, proliferation and mitochondrial metabolism between isogenic AL amyloidosis and multiple myeloma cells that divergently alter their sensitivity to therapy. Overall, our results indicate that BH3 mimetics may be highly effective therapies for AL amyloidosis that exploit inherent and induced dependencies on pro-survival proteins.

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Analysis for expression of genes in multiple myeloma cells treated with PRIMA-1Met or dimethyl sulfoxide (DMSO) control

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