Involvement of Fanconi anemia genes FANCD2 and FANCF in the molecular basis of drug resistance in leukemia

Yao, Chenjiao; Du, Wei; Chen, Haibiug; Xiao, Sheng; Huang, Lihua; Chen, Fangping

doi:10.3892/mmr.2015.3288

Cited by 14 publications

(14 citation statements)

References 12 publications

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“…The ADR doses used in vitro were dependent on the survival of the K562 and K562/ADR cells. According to the results of previous experiments by the authors, pre-treatment with ADR at 2 µM consistently enhanced toxicity in K562 cell lines but not in K562/ADR cell lines (11). Therefore, 2 µM ADR and 5 µM Olaparib were selected for use in further experiments.…”

Section: Discussionmentioning

confidence: 67%

“…Previously published studies by the authors have revealed that the Fanconi anemia (FA)/BRCA signaling pathway is involved in the acquired ADR resistance of leukemia cells (11), and that extensive crosstalk exists within the DNA repair pathway (12). PARP1 inhibitors can strengthen DNA damage when combined with traditional chemotherapy drugs.…”

Section: Introductionmentioning

confidence: 99%

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PARP inhibitor re‑sensitizes Adriamycin resistant leukemia cells through DNA damage and apoptosis

Xiao

Yuan

et al. 2018

Mol Med Report

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Resistance to Adriamycin (ADR) is an increasing problem in the treatment of leukemia and the development of novel therapeutic strategies is becoming increasingly important. Olaparib is a poly (adenosine diphosphate-ribose) polymerase (PARP) 1 inhibitor, which has promising antitumor activity in patients with metastatic breast cancer and germline BRCA mutations. Previously published studies have indicated that Olaparib is able to overcome drug resistance in cancer; however, its underlying mechanism of action is yet to be elucidated. The aim of the present study was to explore the mechanism underlying re-sensitization. Annexin V-propidium iodide staining indicated that the percentage of apoptotic ADR resistant cells was markedly increased and the cell cycle was blocked at the G2/M-phase following treatment with ADR combined with Olaparib, when compared with the control group. The alkaline comet assay demonstrated that ADR combined with Olaparib significantly upregulated the induction of the DNA damage response in ADR-resistant cells. Western blot analysis revealed that the protein expression of γ-H2A histone family member X, cleaved PARP, caspase 3 and cleaved caspase 3 was markedly enhanced, while the cell cycle-associated protein cyclin B1 was downregulated in K562/ADR cells following treatment with a combination of ADR and Olaparib. Similar synergistic cytotoxicity was observed in blood mononuclear cells, which were isolated from patients with chemotherapy-resistant leukemia. As Olaparib is available for clinical use, the results of the present study provide a rationale for the development of Olaparib combinational therapies for cases of ADR resistant leukemia.

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Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

PARP inhibitor re‑sensitizes Adriamycin resistant leukemia cells through DNA damage and apoptosis

Xiao

Yuan

et al. 2018

Mol Med Report

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“…Furthermore, unsupervised clustering was performed with scRNA-seq data from patient B using the SC3 pipeline (version 1.12.0) (19). The functions of DGEs were determined through a literature review (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)…”

Section: Gene Fusion Predictionmentioning

confidence: 99%

Single‑cell RNA sequencing of t(8;21) acute myeloid leukemia for risk prediction

Xiong

Huang

et al. 2020

Oncol Rep

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Single-cell RNA sequencing (scRNA-seq) of bone marrow or peripheral blood samples from patients with acute myeloid leukemia (AML) enables the characterization of heterogeneous malignant cells. A total of 87 cells from two patients with t(8;21) AML were analyzed using scRNA-seq. Clustering methods were used to separate leukemia cells into different sub-populations, and the expression patterns of specific marker genes were used to annotate these populations. Among the 31 differentially expressed genes in the cells of a patient who relapsed after hematopoietic stem cell transplantation, 13 genes were identified to be associated with leukemia. Furthermore, three genes, namely AT-rich interaction domain 2, lysine methyltransferase 2A and synaptotagmin binding cytoplasmic RNA interacting protein were validated as possible prognostic biomarkers using two bulk expression datasets. Taking advantage of scRNA-seq, the results of the present study may provide clinicians with several possible biomarkers to predict the prognostic outcomes of t(8;21) AML.

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“…Patients with a disrupted structure of FANCD2, mainly carriers of Fanconi anemia, have higher risk of cancer development [64,65]. The most frequent cancer types related to FANCD2 are ovarian [66], hepatic [67], lung [68], breast cancer [69] and leukemia [70]. FANCD2 co-localizes with RAD51a following DNA damage is an indication that FANCD2 and RAD51a share roles in DNA repair through physical interactions [16,17,71].…”

Section: In Silico Model For the Rad51a Interaction With Fancd2mentioning

confidence: 99%

In silico Characterization of Rad51a Interactions with Cancer-Related Proteins

e¹

2019

J Genet Genome Res

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RAD51a is a highly conserved protein and its major role is the repair of DNA double strand breaks. Endogenous species are generated during normal cell metabolic activities and can cause damage to DNA, as well as several environmental factors. The interactions RAD51a perform with other proteins help the maintenance of oncogenetic metabolism within cells. RAD51a interacts with PCNA, FANCD2 and ABL1, among many other cancer-related proteins. PCNA acts as a DNA clamp and is related to the replication process, FANCD2 arrests DNA replication fork progression in response to DNA damage and ABL1 is a proto-oncogene related to cell differentiation. Protein-protein interactions (PPIs) are governed by the presence of hot spots within the interface of interaction. Identifying residues directly involved in PPIs enables the likelihood of modulating such complexes with biologically active small molecules such as synthetic peptides, which leads to a new era of diseases treatment. Here, we use an in silico approach to determine the best free-energy of interaction between RAD51a and the targeted cancer-related proteins PCNA, FANCD2 and two chains of ABL1. We propose an interaction interface between RA-D51a and those proteins and identified hot spots that could be useful to understand the molecular basis of their interaction. We believe that further studies may find small-targeted molecules with therapeutics properties that could modulate those interactions and increase our knowledge regarding the complex trait diseases such as cancer.

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Involvement of Fanconi anemia genes FANCD2 and FANCF in the molecular basis of drug resistance in leukemia

Cited by 14 publications

References 12 publications

PARP inhibitor re‑sensitizes Adriamycin resistant leukemia cells through DNA damage and apoptosis

PARP inhibitor re‑sensitizes Adriamycin resistant leukemia cells through DNA damage and apoptosis

Single‑cell RNA sequencing of t(8;21) acute myeloid leukemia for risk prediction

In silico Characterization of Rad51a Interactions with Cancer-Related Proteins

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