Drug Targeting of Genomic Instability in Multiple Myeloma

Beksaç, Meral; Balli, Sevinc; Yildiz, Dilara Akçora

doi:10.3389/fgene.2020.00228

Cited by 13 publications

(10 citation statements)

References 66 publications

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“…Elevated GI represents a therapeutic vulnerability of MM PCs; accordingly, small molecule inhibitors targeting PARP or Aurora kinases, as well as spindle kinase inhibitors have been successfully tested in MM preclinical models and in early phase I/II trials; moreover, ATM, ATR kinase inhibitors, and DNA helicase inhibitors appear to be promising agents, displaying strong synergy in patients with highly refractory MM when combined with DNA-damaging agents, platinum derivatives, immunomodulators, and proteasome inhibitors [ 107 ].…”

Section: Future Perspectivesmentioning

confidence: 99%

Genomic Instability in Multiple Myeloma: A “Non-Coding RNA” Perspective

Taìana

Cantafio

Favasuli

et al. 2021

Cancers

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Multiple myeloma (MM) is a complex hematological malignancy characterized by abnormal proliferation of malignant plasma cells (PCs) within a permissive bone marrow microenvironment. The pathogenesis of MM is unequivocally linked to the acquisition of genomic instability (GI), which indicates the tendency of tumor cells to accumulate a wide repertoire of genetic alterations. Such alterations can even be detected at the premalignant stages of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) and, overall, contribute to the acquisition of the malignant traits underlying disease progression. The molecular basis of GI remains unclear, with replication stress and deregulation of DNA damage repair pathways representing the most documented mechanisms. The discovery that non-coding RNA molecules are deeply dysregulated in MM and can target pivotal components of GI pathways has introduced a further layer of complexity to the GI scenario in this disease. In this review, we will summarize available information on the molecular determinants of GI in MM, focusing on the role of non-coding RNAs as novel means to tackle GI for therapeutic intervention.

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Section: Future Perspectivesmentioning

confidence: 99%

Genomic Instability in Multiple Myeloma: A “Non-Coding RNA” Perspective

Taìana

Cantafio

Favasuli

et al. 2021

Cancers

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“…In addition, we identified that CHEK1 activated NEK2 (data not shown), an established MM CIN marker reported in our previous study [ 26 ], while NEK2 stimulated CIN in cancer cells by regulating CEP250, a core centrosomal protein essential for centriole–centriole cohesion [ 42 , 43 ]. In MM, CIN is accompanied by replication errors, leading to impaired DNA repair characterized by increased expression of DNA repair genes, including ATM, ATR, RAD51, and others [ 44 ]. Our unpublished data revealed that in MM cells, CHEK1 -OE upregulated RAD51, indicating the additional involvement of CHEK1 in DNA repair signaling.…”

Section: Discussionmentioning

confidence: 99%

CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma

Wang

Tang

et al. 2021

Mol Cancer

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Background Multiple myeloma (MM) is still incurable and characterized by clonal expansion of plasma cells in the bone marrow (BM). Therefore, effective therapeutic interventions must target both myeloma cells and the BM niche. Methods Cell proliferation, drug resistance, and chromosomal instability (CIN) induced by CHEK1 were confirmed by Giemsa staining, exon sequencing, immunofluorescence and xenograft model in vivo. Bone lesion was evaluated by Tartrate-resistant acid phosphatase (TRAP) staining. The existence of circCHEK1_246aa was evaluated by qPCR, Sanger sequencing and Mass Spectrometer. Results We demonstrated that CHEK1 expression was significantly increased in human MM samples relative to normal plasma cells, and that in MM patients, high CHEK1 expression was associated with poor outcomes. Increased CHEK1 expression induced MM cellular proliferation and evoked drug-resistance in vitro and in vivo. CHEK1-mediated increases in cell proliferation and drug resistance were due in part to CHEK1-induced CIN. CHEK1 activated CIN, partly by phosphorylating CEP170. Interestingly, CHEK1 promoted osteoclast differentiation by upregulating NFATc1 expression. Intriguingly, we discovered that MM cells expressed circCHEK1_246aa, a circular CHEK1 RNA, which encoded and was translated to the CHEK1 kinase catalytic center. Transfection of circCHEK1_246aa increased MM CIN and osteoclast differentiation similarly to CHEK1 overexpression, suggesting that MM cells could secrete circCHEK1_246aa in the BM niche to increase the invasive potential of MM cells and promote osteoclast differentiation. Conclusions Our findings suggest that targeting the enzymatic catalytic center encoded by CHEK1 mRNA and circCHEK1_246aa is a promising therapeutic modality to target both MM cells and BM niche.

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“…Dynamic genomic instability is known to contribute to disease progression and patient response to therapy in MM [ 35 , 36 ]. Telomere molecular and structural characteristics have been shown to hold useful information regarding disease aggressiveness and may serve as a potential guide for therapeutic intervention [ 23 , 24 , 25 , 36 , 37 , 38 ]. Indeed, some current therapeutic approaches aim to create synthetic lethal interactions in MM cells [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma

Rangel‐Pozzo

Lal

et al. 2021

Cancers

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The prognosis of multiple myeloma (MM), an incurable B-cell malignancy, has significantly improved through the introduction of novel therapeutic modalities. Myeloma prognosis is essentially determined by cytogenetics, both at diagnosis and at disease progression. However, for a large cohort of patients, cytogenetic analysis is not always available. In addition, myeloma patients with favorable cytogenetics can display an aggressive clinical course. Therefore, it is necessary to develop additional prognostic and predictive markers for this disease to allow for patient risk stratification and personalized clinical decision-making. Genomic instability is a prominent characteristic in MM, and we have previously shown that the three-dimensional (3D) nuclear organization of telomeres is a marker of both genomic instability and genetic heterogeneity in myeloma. In this study, we compared in a longitudinal prospective study blindly the 3D telomeric profiles from bone marrow samples of 214 initially treatment-naïve patients with either monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or MM, with a minimum follow-up of 5 years. Here, we report distinctive 3D telomeric profiles correlating with disease aggressiveness and patient response to treatment in MM patients, and also distinctive 3D telomeric profiles for disease progression in smoldering multiple myeloma patients. In particular, lower average intensity (telomere length, below 13,500 arbitrary units) and increased number of telomere aggregates are associated with shorter survival and could be used as a prognostic factor to identify high-risk SMM and MM patients.

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Drug Targeting of Genomic Instability in Multiple Myeloma

Cited by 13 publications

References 66 publications

Genomic Instability in Multiple Myeloma: A “Non-Coding RNA” Perspective

Genomic Instability in Multiple Myeloma: A “Non-Coding RNA” Perspective

CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma

Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma

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