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Clinical drug resistance linked to reversible phenotypic transition and epigenetic alteration in multiple myeloma

ABSTRACT: The development of proteasome inhibitors (PIs) for the treatment of multiple myeloma (MM) has dramatically increased treatment responses and improved survival. The first-in-class PI, bortezomib, was used in a twice-weekly intravenous as a sustained single or combinational regimen for relapsed and subsequently for newly diagnosed MM. The relatively rapid acquisition of drug resistance to PI treatment remains a crucial obstacle. Gradual familiarity with toxicity and optimizing dose schedules have formed the current use of PIs as key components in promoting response and eliminating resistance. Combination therapies and schedule adaptation to once-weekly use of PIs have meanwhile been shown to be both more tolerable and highly efficacious. Interestingly, patients may remain sensitive to PIs after relapse of initial therapy, implying that PI resistance is reversible and suggest a previously unrecognized drug resistance mechanism via epigenetic changes that may be intrinsic to PI treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE136725 | GEO | 2021/02/24

REPOSITORIES: GEO

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Project description:Multiple myeloma (MM) is a malignant plasma cell (PC) dyscrasia characterized by heterogeneous biological features and genetic alterations, resulting in a wide range of disease courses. Despite all the therapeutic strategies developed in the last three decades, MM is still incurable, and almost all patients will inevitably experience disease progression and eventually relapse. Among all the genetic abnormalities, the amplification of the 1q21 region is one of the most frequent lesions occurring in malignant PCs and it has become a new prognostic factor in MM patients. Furthermore, the incidence of gain and/or amplification of the 1q21 locus (1q21+) increases with disease progression. It can be detected in around 30-45% of patients with smoldering MM (SMM) and newly diagnosed MM (NDMM), and in around 70% of relapsed/refractory MM patients. Moreover, the impact of 1q21 on disease progression at an early stage has not been widely investigated. Few studies have suggested that the acquisition of extra 1q21 copies may play a role in disease progression. In fact, SMM patients with 1q21+ may be more likely to progress to MM than patients without 1q21+. Recent studies have demonstrated that the 1q21 copy number has a different impact on the responsiveness to MM treatments, especially proteasome inhibitors (PIs). Throughout the years, the implementation of PIs drugs as part of standard MM therapy has continued to improve the quality of life and clinical outcomes of MM patients. However, innate and acquired resistance to PIs limits their long-term clinical utility. Furthermore, additional copies of 1q21 have been associated with PI resistance and recurrence of the disease in patients with 1q21+. Several genes are known to be deregulated upon the amplification of the 1q21 locus, however, the pathogenic mechanism of how those genes drive disease progression and contribute to the poor outcome in patients with 1q21+ and their possible role as druggable targets is not fully understood. In this study, we analyzed purified CD138+ bone marrow PCs from 11 SMM and 18 NDMM patients to identify genes whose expressions are deregulated in patients with 1q21+ in correlation with the number of copies and their putative role in drug response.

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Clinical drug resistance linked to reversible phenotypic transition and epigenetic alteration in multiple myeloma

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