Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma

Dupéré-Richér, Daphne; Licht, Jonathan D.

doi:10.1097/moh.0000000000000358

Cited by 39 publications

(36 citation statements)

References 109 publications

(110 reference statements)

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“…Global analysis of miRNA expression in MM has also revealed a clinical relevance as the analysis could correlate miRNA expression to disease progression, molecular subtype, survival and response to treatment (115)(116)(117)(118)(119)(120). More recently, several whole genome sequencing and gene expression studies have underpinned that histone PTMs can model chromatin structure driving complex regulatory networks (121). However, epigenetic mechanisms are far from reaching enough evidence to be proposed as clinical-grade prognostic markers and further work and technological advances are needed before this can happen.…”

Section: Newly Diagnosed Myelomamentioning

confidence: 99%

Next-Generation Sequencing for Clinical Management of Multiple Myeloma: Ready for Prime Time?

et al. 2020

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Personalized treatment is an attractive strategy that promises increased efficacy with reduced side effects in cancer. The feasibility of such an approach has been greatly boosted by next-generation sequencing (NGS) techniques, which can return detailed information on the genome and on the transcriptome of each patient's tumor, thus highlighting biomarkers of response or druggable targets that may differ from case to case. However, while the number of cancers sequenced is growing exponentially, much fewer cases are amenable to a molecularly-guided treatment outside of clinical trials to date. In multiple myeloma, genomic analysis shows a variety of gene mutations, aneuploidies, segmental copy-number changes, translocations that are extremely heterogeneous, and more numerous than other hematological malignancies. Currently, in routine clinical practice we employ reduced FISH panels that only capture three high-risk features as part of the R-ISS. On the contrary, recent advances have suggested that extending genomic analysis to the full spectrum of recurrent mutations and structural abnormalities in multiple myeloma may have biological and clinical implications. Furthermore, increased efficacy of novel treatments can now produce deeper responses, and standard methods do not have enough sensitivity to stratify patients in complete biochemical remission. Consequently, NGS techniques have been developed to monitor the size of the clone to a sensitivity of up to a cell in a million after treatment. However, even these techniques are not within reach of standard laboratories. In this review we will recapitulate recent advances in multiple myeloma genomics, with special focus on the ones that may have immediate translational impact. We will analyze the benefits and pitfalls of NGS-based diagnostics, highlighting crucial aspects that will need to be taken into account before this can be implemented in most laboratories. We will make the point that a new era in myeloma diagnostics and minimal residual disease monitoring is close and conventional genetic testing will not be able to return the required information. This will mandate that even in routine practice NGS should soon be adopted owing to a higher informative potential with increasing clinical benefits.

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Section: Newly Diagnosed Myelomamentioning

confidence: 99%

Next-Generation Sequencing for Clinical Management of Multiple Myeloma: Ready for Prime Time?

et al. 2020

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“…Furthermore, the N-terminal tails are subject to methylation, acetylation and phosphorylation, impacting the gene transcription [ 67 , 69 , 70 ]. The emerging data are suggesting a critical role of histone posttranslational modifications in MM pathogenesis [ 71 ]. Altered posttranslational modifications were found to deregulate miRNAs in MM cells.…”

Section: Epigenetics Of MMmentioning

confidence: 99%

Role of microRNAs in Diagnosis, Prognosis and Management of Multiple Myeloma

Soliman

Teoh

Mahakkanukrauh

et al. 2020

IJMS

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Multiple myeloma (MM) is a cancerous bone disease characterized by malignant transformation of plasma cells in the bone marrow. MM is considered to be the second most common blood malignancy, with 20,000 new cases reported every year in the USA. Extensive research is currently enduring to validate diagnostic and therapeutic means to manage MM. microRNAs (miRNAs) were shown to be dysregulated in MM cases and to have a potential role in either progression or suppression of MM. Therefore, researchers investigated miRNAs levels in MM plasma cells and created tools to test their impact on tumor growth. In the present review, we discuss the most recently discovered miRNAs and their regulation in MM. Furthermore, we emphasized utilizing miRNAs as potential targets in the diagnosis, prognosis and treatment of MM, which can be useful for future clinical management.

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“…Supporting the importance of epigenetic mechanisms in MM pathogenesis, genetic alterations affecting components of epigenetic machineries i.e. epigenetic modifiers, mediators and substrates such as histone proteins, have been reported in MM [ 13 – 15 ]. In addition, deregulated expression and function of epigenetic modifiers such as the enhancer of zeste homolog 2 (EZH2) [ 16 – 18 ], the multiple myeloma SET domain containing-protein (MMSET) [ 19 , 20 ] and members of the Jumonji C-domain-containing histone demethylases KDM6B [ 21 ] and KDM3A [ 22 ] are frequently observed in MM.…”

Section: Introductionmentioning

confidence: 99%

The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomains

et al. 2017

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Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.

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Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma

Cited by 39 publications

References 109 publications

Next-Generation Sequencing for Clinical Management of Multiple Myeloma: Ready for Prime Time?

Next-Generation Sequencing for Clinical Management of Multiple Myeloma: Ready for Prime Time?

Role of microRNAs in Diagnosis, Prognosis and Management of Multiple Myeloma

The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomains

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