Microsatellite Instability and Promoter Hypermethylation of DNA repair genes in Hematologic Malignancies: a forthcoming direction toward diagnostics

Bhattacharya, Priyanjali; Patel, Trupti

doi:10.1080/10245332.2017.1354428

Cited by 15 publications

(9 citation statements)

References 42 publications

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“…Research shows that MMR ensures replication fidelity by correcting mismatches generated during DNA replication 37, 38. DNA MMR and direct reversal of damage (DRD) are two repair mechanisms that help in the removal of faulty base pairs and alkyl adduct formation, respectively, to avoid long-term effects of toxicity, tumorigenesis, and mutagenesis 39 …”

Section: Discussionmentioning

confidence: 99%

miR675 Accelerates Malignant Transformation of Mesenchymal Stem Cells by Blocking DNA Mismatch Repair

Song

Jiang

et al. 2019

Molecular Therapy - Nucleic Acids

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miR675 is highly expressed in several human tumor tissues and positively regulates cell progression. Herein, we demonstrate that miR675 promotes malignant transformation of human mesenchymal stem cells. Mechanistically, we reveal that miR675 enhances the expression of the polyubiquitin-binding protein p62. Intriguingly, P62 competes with SETD2 to bind histone H3 and then significantly reduces SETD2-binding capacity to substrate histone H3, triggering drastically the reduction of three methylation on histone H3 36th lysine (H3K36me3). Thereby, the H3K36me3-hMSH6-SKP2 triplex complex is significantly decreased. Notably, the ternary complex’s occupancy capacity on chromosome is absolutely reduced, preventing it from DNA damage repair. By virtue of the reductive degradation ability of SKP2 for aging histone H3.3 bound to mismatch DNA, the aging histone H3.3 repair is delayed. Therefore, the mismatch DNA escapes from repair, triggering the abnormal expression of several cell cycle-related genes and causing the malignant transformation of mesenchymal stem cells. These observations strongly suggest understanding the novel functions of miR675 will help in the development of novel therapeutic approaches in a broad range of cancer types.

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Section: Discussionmentioning

confidence: 99%

miR675 Accelerates Malignant Transformation of Mesenchymal Stem Cells by Blocking DNA Mismatch Repair

Song

Jiang

et al. 2019

Molecular Therapy - Nucleic Acids

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“…Valdez et al [146] have recently shown that the combined use of HMA, HDACi, and PARPi resulted in extensive DNA damage, double-strand breaks (DSBs), and apoptosis. Furthermore, evidence is accumulating that links the microsatellite instability (MSI) phenotype of hematological tumors to the disruption of the mismatch repair pathway by promoter hypermethylation of the pathway's own genes [147]. Thus, it is reasonable to speculate further that, as observed in solid tumors, the MSI phenotype might confer some hematological neoplasms with higher rates of ICI responses, through enhancement of neoantigen presentation [148].…”

Section: Discussionmentioning

confidence: 99%

The DNA methylation landscape of hematological malignancies: an update

2020

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The rapid advances in high‐throughput sequencing technologies have made it more evident that epigenetic modifications orchestrate a plethora of complex biological processes. During the last decade, we have gained significant knowledge about a wide range of epigenetic changes that crucially contribute to some of the most aggressive forms of leukemia, lymphoma, and myelodysplastic syndromes. DNA methylation is a key epigenetic player in the abnormal initiation, development, and progression of these malignancies, often acting in synergy with other epigenetic alterations. It also contributes to the acquisition of drug resistance. In this review, we summarize the role of DNA methylation in hematological malignancies described in the current literature. We discuss in detail the dual role of DNA methylation in normal and aberrant hematopoiesis, as well as the involvement of this type of epigenetic change in other aspects of the disease. Finally, we present a comprehensive overview of the main clinical implications, including a discussion of the therapeutic strategies that regulate or reverse aberrant DNA methylation patterns in hematological malignancies, including their combination with (chemo)immunotherapy.

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“…Several repair genes ( MSH2, MSH3, MSH6, MLH1, MLH3, PMS1 and PMS2 ) are involved in this process and work by forming heterodimers. The interaction between mismatch recognition complexes and other proteins such as helicase, proliferating cell nuclear antigen, replication protein A, exonuclease 1 is required for the rectification of base-pair alterations, insertion-deletion loops and hetero-duplexes instigated during replication and recombination (9). MMR genes aberrations can be investigated by immunohistochemistry (IHC) for MMR proteins, which is a quick and simple assay to recognize MMR status (10–12).…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical mismatch repair proteins expression as a tool to predict the melanoma immunotherapy response

et al. 2019

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In difference to other solid malignancies, the identification of biomarkers for the prediction of malignant melanoma (MM) response to immunotherapy is limited. The aim of the current study was to evaluate the immunohistochemical (IHC) expression of MMR proteins in a cohort of MM metastatic patients receiving anti PD-1 treatments. The therapeutic response of patients was also retrospectively assessed. The cohort of the current study included 14 patients with advanced MM that had received anti PD-1 from January 2014 to December 2016 (12 males, 2 females; average age, 71 years; age range, 47–88 years). IHC analysis of MLH1, PMS2, MSH2 and MSH6 proteins was performed on paraffin-embedded primary tumor samples from each patient and on the 23 available metastasis specimens obtained from the Division of Pathology (University of Modena and Reggio Emilia). The results revealed that 7% of the primary melanoma tissue obtained from the patient cohort exhibited the loss of expression of at least one MMR protein. Three samples from one patient, including one primary melanoma and two metastases, exhibited no MSH6 expression and had the most successful response to anti PD-1 treatment, with a progression-free survival and overall survival of 956 and 2,546 days, respectively. In conclusion, the assessment of MMR protein expression represents a potential predictive marker that may have critical importance for patients with primary and metastatic MM, primarily as criterion for the adoption of immunotherapy treatments.

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Microsatellite Instability and Promoter Hypermethylation of DNA repair genes in Hematologic Malignancies: a forthcoming direction toward diagnostics

Abstract: The presence of specific microsatellite marker hyper-mutability and consistent promoter hypermethylation in leukemia or lymphoma can be considered as a part of routine diagnostic test in clinical laboratories.

Cited by 15 publications

References 42 publications

miR675 Accelerates Malignant Transformation of Mesenchymal Stem Cells by Blocking DNA Mismatch Repair

miR675 Accelerates Malignant Transformation of Mesenchymal Stem Cells by Blocking DNA Mismatch Repair

The DNA methylation landscape of hematological malignancies: an update

Immunohistochemical mismatch repair proteins expression as a tool to predict the melanoma immunotherapy response

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