Chromatin structure, transcriptional activity and DNA repair efficiency affect the outcome of chemotherapy in multiple myeloma

Γκοτζαμανίδου, Μαρία; Sfikakis, Petros P.; Kyrtopoulos, Soterios A.; Bamia, Christina; Dimopoulos, Meletios Α.; Souliotis, V.L.

doi:10.1038/bjc.2014.410

Cited by 20 publications

(28 citation statements)

References 51 publications

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“…Little is known about the effects of melphalan on normal epithelium, but in cancer cells, melphalan induces oxidative stress and upregulates a wide range of apoptosis-related genes [8, 29], consistent with our findings of EDA2R upregulation. EDA2R encodes a TNF receptor that mediates the activation of NF-κB and jun-N-terminal (JNK) pathways, which lead to caspase-initiated apoptosis.…”

Section: Discussionsupporting

confidence: 88%

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Molecular Characteristics of High-Dose Melphalan Associated Oral Mucositis in Patients with Multiple Myeloma: A Gene Expression Study on Human Mucosa

et al. 2017

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BackgroundToxicity of the oral and gastrointestinal mucosa induced by high-dose melphalan is a clinical challenge with no documented prophylactic interventions or predictive tests. The aim of this study was to describe molecular changes in human oral mucosa and to identify biomarkers correlated with the grade of clinical mucositis.Methods and FindingsTen patients with multiple myeloma (MM) were included. For each patient, we acquired three buccal biopsies, one before, one at 2 days, and one at 20 days after high-dose melphalan administration. We also acquired buccal biopsies from 10 healthy individuals that served as controls. We analyzed the biopsies for global gene expression and performed an immunohistochemical analysis to determine HLA-DRB5 expression. We evaluated associations between clinical mucositis and gene expression profiles. Compared to gene expression levels before and 20 days after therapy, at two days after melphalan treatment, we found gene regulation in the p53 and TNF pathways (MDM2, INPPD5, TIGAR), which favored anti-apoptotic defense, and upregulation of immunoregulatory genes (TREM2, LAMP3) in mucosal dendritic cells. This upregulation was independent of clinical mucositis. HLA-DRB1 and HLA-DRB5 (surface receptors on dendritic cells) were expressed at low levels in all patients with MM, in the subgroup of patients with ulcerative mucositis (UM), and in controls; in contrast, the subgroup with low-grade mucositis (NM) displayed 5–6 fold increases in HLA-DRB1 and HLA-DRB5 expression in the first two biopsies, independent of melphalan treatment. Moreover, different splice variants of HLA-DRB1 were expressed in the UM and NM subgroups.ConclusionsOur results revealed that, among patients with MM, immunoregulatory genes and genes involved in defense against apoptosis were affected immediately after melphalan administration, independent of the presence of clinical mucositis. Furthermore, our results suggested that the expression levels of HLA-DRB1 and HLA-DRB5 may serve as potential predictive biomarkers for mucositis severity.

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Section: Discussionsupporting

confidence: 88%

“…The mechanisms of action and metabolism of melphalan are well-described [8]. Melphalan alkylates DNA, which causes cross-links to form between DNA strands, and subsequently, DNA is degraded through apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Molecular Characteristics of High-Dose Melphalan Associated Oral Mucositis in Patients with Multiple Myeloma: A Gene Expression Study on Human Mucosa

et al. 2017

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“…43 In the present study, the kinetics of N-ras-specific monoadducts repair were followed for up to 48 hours after treatment of RPMI 8226 and LR5 cells with melphalan by using Southern blot analysis ( Figure 1A). Similar formation of monoadducts was observed in both cell types at the end of the 5-minute treatment ( Figure 1B).…”

Section: Resultsmentioning

confidence: 95%

DNA repair of myeloma plasma cells correlates with clinical outcome: the effect of the nonhomologous end-joining inhibitor SCR7

Γκοτζαμανίδου

Terpos

Bamia

et al. 2016

Blood

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Key Points• Responders to melphalan therapy are characterized by slower rates of NER and DSB/R mechanisms and higher apoptotic rates.• The DSB/R inhibitor SCR7 enhances cytotoxicity of melphalan against myeloma plasma cells.DNA repair activity of malignant cells seems to influence therapeutic outcome and patients' survival. Herein, we investigated the mechanistic basis for the link between DNA repair efficiency and response to antimyeloma therapy. Nucleotide excision repair (NER), interstrand cross-links repair (ICL/R), double-strand breaks repair (DSB/R), and chromatin structure were evaluated in multiple myeloma (MM) cell lines (melphalan-sensitive RPMI8226; melphalan-resistant LR5) and bone marrow plasma cells (BMPCs) from MM patients who responded (n 5 17) or did not respond (n 5 9) to subsequent melphalan therapy. The effect of DSB/R inhibition was also evaluated. Responders' BMPCs showed slower rates of NER and DSB/R (P < .0022), similar rates of ICL/R, and more condensed chromatin structure compared with nonresponders. Moreover, apoptosis rates of BMPCs were inversely correlated with individual DNA repair efficiency and were higher in responders' cells compared with those of nonresponders (P 5 .0011). Similarly, RPMI8226 cells showed slower rates of NER and DSB/R, comparable rates of ICL/R, more condensed chromatin structure, and higher sensitivity than LR5 cells. Interestingly, cotreatment of BMPCs or cell lines with DSB/R inhibitors significantly reduced the rates of DSB/R and increased melphalan sensitivity of the cells, with the nonhomologous end-joining inhibitor SCR7 showing the strongest effect. Together, responders' BMPCs are characterized by lower efficiencies of NER and DSB/R mechanisms, resulting in higher accumulation of the extremely cytotoxic ICLs and DSBs lesions, which in turn triggers the induction of the apoptotic pathway. Moreover, the enhancement of melphalan cytotoxicity by DSB/R inhibition offers a promising strategy toward improvement of existing antimyeloma regimens. (Blood. 2016;128(9):1214-1225

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“…A poorer differentiation grade of the primary tumour implicates a better response to nCRT. A possible explanation could be that poorly differentiated tumours are more susceptible to nCRT because of a higher turnover of cells and consequently a higher susceptibility for DNA damage and apoptosis [34]. Female gender leading to a higher probability of pCR is a striking finding, with no strong supporting evidence from the literature.…”

Section: Discussionmentioning

confidence: 95%

Nomogram for predicting pathologically complete response after neoadjuvant chemoradiotherapy for oesophageal cancer

Toxopeus

Nieboer

Shapiro

et al. 2015

Radiotherapy and Oncology

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Chromatin structure, transcriptional activity and DNA repair efficiency affect the outcome of chemotherapy in multiple myeloma

Cited by 20 publications

References 51 publications

Molecular Characteristics of High-Dose Melphalan Associated Oral Mucositis in Patients with Multiple Myeloma: A Gene Expression Study on Human Mucosa

Molecular Characteristics of High-Dose Melphalan Associated Oral Mucositis in Patients with Multiple Myeloma: A Gene Expression Study on Human Mucosa

DNA repair of myeloma plasma cells correlates with clinical outcome: the effect of the nonhomologous end-joining inhibitor SCR7

Nomogram for predicting pathologically complete response after neoadjuvant chemoradiotherapy for oesophageal cancer

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