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Identification of PSMB4 and PSMD4 as novel target correlated with 1q21 amp in patients with smoldering myeloma and multiple myeloma.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227907 | GEO | 2024/02/07

REPOSITORIES: GEO

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Project description:Smoldering myeloma (SMM) is a pre-malignant monoclonal gammopathy with a 10% annual risk to progress to active multiple myeloma (MM). SMM diagnostic criteria, as well of those of others monoclonal gammopathies, have been updated by the International Myeloma Working Group (IMWG) in 2014. In particular, the previously defined “ultra high-risk” SMM (characterized by the presence of specific biomarkers associated with a ≥ 80% risk of progression to symptomatic MM within 2 years) has been included among patients with active MM. SMM is biologically heterogeneous, including a subset of patients with biological pre-malignancy and a subset with biological malignancy who have not yet developed organ damage, defined as onset of the classical CRAB criteria or Myeloma Defining Events (MDE). Thus, SMM encompassed patients with a very low rate of progression to symptomatic MM, similar to patients with monoclonal gammopathy of uncertain significance (MGUS), as well as patients who acquired organ damage and progress to active MM within the first year from diagnosis. The molecular mechanisms involved in the SMM to MM progression are still far to be fully understood. Genomic studies indicate that the genetic alterations that characterize MM patients are already present in SMM ones, who present similar mutational and copy number alteration load. However, few data are available on the transcriptional profiles of SMM patients in relationship to the progression to active MM, overall indicating minimal differential expression either in coding or non-coding RNA fraction. To date, robust data are still lacking which describe the transcriptional profiles of plasma cells (PCs) from paired samples obtained at the time of SMM and at MM onset. Herein, we compared the transcriptome of purified CD138+ PCs from paired samples of SMM patients progressed to active MM (P-SMM), aimed at describing any possible common transcriptional discrepancy that may help to understand the intra-patient disease evolution; at the same time, we investigated the transcriptional differences between P-SMM and a subset of non-progressed SMM (NP-SMM) at a minimum of 36 months.

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Identification of PSMB4 and PSMD4 as novel target correlated with 1q21 amp in patients with smoldering myeloma and multiple myeloma.

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