High PARP-1 expression Predicts Poor Survival in Acute Myeloid Leukemia and PARP-1 Inhibitor and SAHA-Bendamustine Hybrid Inhibitor Combination Treatment Synergistically Enhances Anti-Tumor Effects

Li, Xia; Li, Chenying; Jin, Jie; Wang, Jinghan

doi:10.1182/blood-2018-99-114344

Cited by 6 publications

(6 citation statements)

References 60 publications

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“…The latest data also confirm that PARP1 was highly expressed in cytogenetically normal AML patients and AML cell lines compared to normal bone marrow cells. It may indicate that PARP1 plays a critical role in the development of AML [4]. Research by Fonfria et al [35] confirms the hypothesis that PARP enzyme activity is a central component of the pathway linking oxidative stress with TRPM2 activation [35].…”

Section: Discussionmentioning

confidence: 84%

Different regulation of PARP1, PARP2, PARP3 and TRPM2 genes expression in acute myeloid leukemia cells

Gil-Kulik

Dudzińska

Radzikowska-Büchner³

et al. 2020

Preprint

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Background: Acute myeloid leukemia (AML) is a heterogenic lethal disorder characterized by the accumulation of abnormal myeloid progenitor cells in the bone marrow which results in hematopoietic failure. Despite various efforts in detection and treatment, many patients with AML die of this cancer. That is why it is important to develop novel therapeutic options, employing strategic target genes involved in apoptosis and tumor progression.Methods: The aim of the study was to evaluate PARP1, PARP2, PARP3, and TRPM2 gene expression at mRNA level using qPCR method in the cells of hematopoietic system of the bone marrow in patients with acute myeloid leukemia, bone marrow collected from healthy patients, peripheral blood of healthy individuals, and hematopoietic stem cells from the peripheral blood after mobilization. Results: The results found that the bone marrow cells of the patients with acute myeloid leukemia (AML) show overexpression of PARP1 and PARP2 genes and decreased TRPM2 gene expression. In the hematopoietic stem cells derived from the normal marrow and peripheral blood after mobilization, the opposite situation was observed, i.e. TRPM2 gene showed increased expression while PARP1 and PARP2 gene expression was reduced. We observed positive correlations between PARP1, PARP2, PARP3, and TRPM2 genes expression in the group of mature mononuclear cells derived from the peripheral blood and in the group of bone marrow-derived cells. In AML cells significant correlations were not observed between the expression of the examined genes. In addition, we observed that the reduced expression of TRPM2 and overexpression of PARP1 are associated with a shorter overall survival of patients, indicating the prognostic significance of these genes expression in AML.Conclusions: Our research suggests that in physiological conditions in the cells of the hematopoietic system there is mutual positive regulation of PARP1, PARP2, PARP3, and TRPM2 genes expression. PARP1, PARP2, and TRPM2 genes at mRNA level deregulate in acute myeloid leukemia cells.

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Section: Discussionmentioning

confidence: 84%

Different regulation of PARP1, PARP2, PARP3 and TRPM2 genes expression in acute myeloid leukemia cells

Gil-Kulik

Dudzińska

Radzikowska-Büchner³

et al. 2020

Preprint

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“…Patients with higher PARP1 mRNA levels had a better response to 5-azacytidine and longer median survival after treatment initiation, suggesting that PARP1 can potentially serve as a guide to therapeutic decisions [119]. However, it exhibits an inverse correlation with prognosis in AML [120]. Other factors, such as ATM, XRCC6, and Lig IV, are also overexpressed in MDS patients as a consequence of some functional polymorphisms in their germlines [121,122].…”

Section: Mdsmentioning

confidence: 99%

Involvement of classic and alternative non-homologous end joining pathways in hematologic malignancies: targeting strategies for treatment

et al. 2021

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Chromosomal translocations are the main etiological factor of hematologic malignancies. These translocations are generally the consequence of aberrant DNA double-strand break (DSB) repair. DSBs arise either exogenously or endogenously in cells and are repaired by major pathways, including non-homologous end-joining (NHEJ), homologous recombination (HR), and other minor pathways such as alternative end-joining (A-EJ). Therefore, defective NHEJ, HR, or A-EJ pathways force hematopoietic cells toward tumorigenesis. As some components of these repair pathways are overactivated in various tumor entities, targeting these pathways in cancer cells can sensitize them, especially resistant clones, to radiation or chemotherapy agents. However, targeted therapy-based studies are currently underway in this area, and furtherly there are some biological pitfalls, clinical issues, and limitations related to these targeted therapies, which need to be considered. This review aimed to investigate the alteration of DNA repair elements of C-NHEJ and A-EJ in hematologic malignancies and evaluate the potential targeted therapies against these pathways.

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“…We observed both an increase in H2AX signal and sensitivity of the cells with a combination of a PARPi and romidepsin compared to that of the individual agents alone (Figure 7C). The romidepsin effect on R-loops could explain multiple studies that have reported increased efficacy combining PARP1 inhibitors with romidepsin (65,66).…”

Section: Discussionmentioning

confidence: 99%

R-Loop–Mediated ssDNA Breaks Accumulate Following Short-Term Exposure to the HDAC Inhibitor Romidepsin

Safari

Litman

Robey

et al. 2021

Molecular Cancer Research

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Histone deacetylase inhibitors (HDACis) induce hyperacetylation of histones by blocking HDAC catalytic sites. Despite regulatory approvals in hematological malignancies, limited solid tumor clinical activity has constrained their potential, arguing for better understanding of mechanisms of action. Multiple activities of HDAC inhibitors have been demonstrated, dependent on cell context, beyond the canonical induction of gene expression. Here, using a clinically relevant exposure duration, we established DNA damage as the dominant signature using the NCI-60 cell line database and then focused on the mechanism by which hyperacetylation induces DNA damage. We identified accumulation of DNA-RNA hybrids (R-loops) following romidepsin-induced histone hyperacetylation, with single-stranded DNA breaks detected by single cell electrophoresis. Our data suggest that transcription-coupled base excision repair (BER) is involved in resolving ssDNA breaks that, when overwhelmed, evolve to lethal dsDNA breaks. We show that inhibition of BER proteins such as PARP will increase dsDNA breaks in this context. These studies establish accumulation of R-loops as a consequence of romidepsin-mediated histone hyperacetylation. We believe that the insights provided will inform design of more effective combination therapy with HDACis for treatment of solid tumors.Implications: Key HDAC inhibitor mechanisms of action remain unknown; we identify accumulation of DNA-RNA hybrids (R-loops) due to chromatin hyperacetylation that provokes single-stranded DNA damage as a first step toward cell death.

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High PARP-1 expression Predicts Poor Survival in Acute Myeloid Leukemia and PARP-1 Inhibitor and SAHA-Bendamustine Hybrid Inhibitor Combination Treatment Synergistically Enhances Anti-Tumor Effects

Cited by 6 publications

References 60 publications

Different regulation of PARP1, PARP2, PARP3 and TRPM2 genes expression in acute myeloid leukemia cells

Different regulation of PARP1, PARP2, PARP3 and TRPM2 genes expression in acute myeloid leukemia cells

Involvement of classic and alternative non-homologous end joining pathways in hematologic malignancies: targeting strategies for treatment

R-Loop–Mediated ssDNA Breaks Accumulate Following Short-Term Exposure to the HDAC Inhibitor Romidepsin

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