A Tangle of Genomic Aberrations Drives Multiple Myeloma and Correlates with Clinical Aggressiveness of the Disease: A Comprehensive Review from a Biological Perspective to Clinical Trial Results

Sessa, Mariarosaria; Cavazzini, Francesco; Cavallari, Maurizio; Rigolin, Gian Matteo; Cuneo, Antonio

doi:10.3390/genes11121453

Cited by 2 publications

(1 citation statement)

References 113 publications

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“…MYC aberrations are strongly involved in MM pathogenesis and correlate with poor clinical outcome and drug resistance [31,36]. MYC plays a critical role in the control of miRNAs expression and, in turn, MYC-regulated miRNAs influence all MYC-driven hallmarks of cancers [37].…”

Section: Discussionmentioning

confidence: 99%

miR-22 Modulates Lenalidomide Activity by Counteracting MYC Addiction in Multiple Myeloma

Caracciolo

Riillo

Juli

et al. 2021

Cancers

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Background: MYC is a master regulator of multiple myeloma (MM) by orchestrating several pro-tumoral pathways, including reprograming of the miRNA transcriptome. MYC is also involved in the acquirement of resistance to anti-MM drugs, including immunomodulatory imide drugs (IMiDs). Methods: In silico analysis was performed on MM proprietary and on public MMRF-CoMMpass datasets. Western blot and chromatin immunoprecipitation (ChIP) experiments were performed to validate miR-22 repression induced by MYC. Cell viability and apoptosis assays were used to evaluate lenalidomide sensitization after miR-22 overexpression. Results: We found an inverse correlation between MYC and miR-22 expression, which is associated with poor outcome in IMiD-treated MM patients. Mechanistically, we showed that MYC represses transcription of miR-22, which, in turn, targets MYC, thus establishing a feed-forward loop. Interestingly, we found that IMiD lenalidomide increases miR-22 expression by reducing MYC repression and, most importantly, that the combination of lenalidomide with miR-22 mimics results in a synergistic direct and NK-mediated cytotoxic activity. Conclusions: Taken together, our findings indicate that: (1) low miR-22 expression could represent a potential predictive biomarker of poor lenalidomide response in MM patients; and (2) miR-22 reduces MYC oncogenic activity, thus triggering a novel synthetic lethality loop, which sensitizes MM cells to lenalidomide.

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Section: Discussionmentioning

confidence: 99%

miR-22 Modulates Lenalidomide Activity by Counteracting MYC Addiction in Multiple Myeloma

Caracciolo

Riillo

Juli

et al. 2021

Cancers

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Stratification of Patients with Multiple Myeloma: State-of-the-Art and Prospects

Aksenova

Zhuk

Stepchenkova

et al. 2022

Клиническая онкогематология

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In recent years, there has been a substantial progress in improving progression-free survival (PFS) and quality of life of multiple myeloma (MM) patients. This has become possible through implementation of novel drugs into clinical practice which were developed on the basis of multiomic molecular genetic studies in MM. The results of these studies also enabled to assess genetic heterogeneity of tumor cells in MM. That allowed to identify types and prevalence of single-nucleotide variations, structural chromosomal aberrations, and abnormal copy numbers of chromosomes in the genome of malignant plasma cells. It was shown that MM patients can have quite different spectra of detected genetic defects in the tumor. High genetic disease heterogeneity is one of the major causes of differences in drug efficacy and PFS. The present review comprehensively discusses the value of some chromosomal aberrations in risk stratification of MM patients. It describes the most prevalent aberrations, also those associated with high and low risk of early MM progression which have already been included in different international prognostic scores. Besides, the additional aberrations were determined which are potentially applicable in clinical practice. Special attention was paid to risk assessment in case a number of different chromosome rearrangements are identified in a patient. The review outlines challenges and prospects of dealing with the information on chromosome rearrangements in choosing the most optimal treatment strategy and assessing of its efficacy. In this context, emphasis is laid on integrating genetic data and such clinical parameters as age, comorbidity, renal failure, bone lesions, indications for autologous hematopoietic stem cell transplantation, etc.

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A Tangle of Genomic Aberrations Drives Multiple Myeloma and Correlates with Clinical Aggressiveness of the Disease: A Comprehensive Review from a Biological Perspective to Clinical Trial Results

Cited by 2 publications

References 113 publications

miR-22 Modulates Lenalidomide Activity by Counteracting MYC Addiction in Multiple Myeloma

miR-22 Modulates Lenalidomide Activity by Counteracting MYC Addiction in Multiple Myeloma

Stratification of Patients with Multiple Myeloma: State-of-the-Art and Prospects

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