The DNA Double-Strand Break Response Is Abnormal in Myeloblasts From Patients With Therapy-Related Acute Myeloid Leukemia
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ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PRJNA231540E-GEOD-52478PRJNA229072PRJNA231541
ORGANISM(S): Homo sapiens
PROVIDER: GSE53251 | GEO | 2013/12/13
SECONDARY ACCESSION(S): PRJNA231540
REPOSITORIES: GEO
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Project description:The complex chromosomal aberrations found in therapy-related acute myeloid leukemia (t-AML) suggest that the DNA double-strand break (DSB) response may be altered. In this study we examined the DNA DSB response of primary bone marrow cells from t-AML patients and performed next-generation sequencing of 37 canonical homologous recombination (HR) and non-homologous end-joining (NHEJ) DNA repair genes, and a subset of DNA damage response genes using tumor and paired normal DNA obtained from t-AML patients. Our results suggest that the majority of t-AML patients (11 of 15) have tumor-cell intrinsic, functional dysregulation of their DSB response. Distinct patterns of abnormal DNA damage response in myeloblasts correlated with acquired genetic alterations in TP53 and the presence of inferred chromothripsis. Furthermore, the presence of trisomy 8 in tumor cells was associated with persistently elevated levels of DSBs. Although tumor-acquired point mutations or small indels in canonical HR and NHEJ genes do not appear to be a dominant means by which t-AML leukemogenesis occurs, our functional studies suggest that an abnormal response to DNA damage is a common finding in t-AML.
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Project description:In order to examine if the upregulation of DNA repair genes on chromosome 8 was associated with the abnormal DSB phenotype observed in trisomy 8 (defined by array CGH or cytogenetics), we compared the mRNA levels of DNA repair genes on chromosome 8 in trisomy 8 t-AML patients versus normal t-AML gammaH2AX responders using gene expression array data. Bone marrow cells taken directly from patients after written informed consent were cryopreserved, RNA extracted, and microarray analysis was performed using Affymetrix U133plus2 chips.
2013-11-19 | E-GEOD-52478 | biostudies-arrayexpress
Project description:In order to examine if the upregulation of DNA repair genes on chromosome 8 was associated with the abnormal DSB phenotype observed in trisomy 8 (defined by array CGH or cytogenetics), we compared the mRNA levels of DNA repair genes on chromosome 8 in trisomy 8 t-AML patients versus normal t-AML gammaH2AX responders using gene expression array data.
2013-11-19 | GSE52478 | GEO
Project description:In order to examine if acquired copy number alterations in DNA repair genes is commonly observed in therapy-related AML, we used this custom built NimbleGen array with dense tiling of probes in 170 DNA repair genes to interrogate paired normal (skin) and tumor (bone marrow) samples.
2013-12-13 | GSE53250 | GEO
Project description:Resistance to imatinib (IM) and other tyrosine kinase inhibitors (TKI)s is an increasing problem in leukemias caused by expression of BCR-ABL1. As chronic myeloid leukemia (CML) cell lines expressing BCR-ABL1 utilize an alternative non-homologous end-joining pathway (ALT NHEJ) to repair DNA double-strand breaks (DSB)s, we asked whether this repair pathway is a novel therapeutic target in TKI-resistant disease. Notably, the steady state levels of two ALT NHEJ proteins, poly-(ADP-ribose) polymerase 1 (PARP1) and DNA ligase III?, were increased in the BCR-ABL1-positive CML cell line K562 and, to a greater extent, in its imatinib-resistant (IMR) derivative. Incubation of these cell lines with a combination of DNA ligase and PARP inhibitors inhibited ALT NHEJ and selectively decreased survival with the effect being greater in the IMR derivative. Similar results were obtained with TKI-resistant derivatives of two hematopoietic cell lines that had been engineered to stably express BCR-ABL1. Together our results show that the sensitivity of cell lines expressing BCR-ABL1 to the combination of DNA ligase and PARP inhibitors correlates with the steady state levels of PARP1 and DNA ligase III?, and ALT NHEJ activity. Importantly, analysis of clinical samples from CML patients confirmed that the expression levels of PARP1 and DNA ligase III? correlated with the sensitivity to the DNA repair inhibitor combination. Thus, the expression levels of PARP1 and DNA ligase III? serve as biomarkers to identify a subgroup of CML patients who may be candidates for therapies that target the ALT NHEJ pathway when treatment with TKIs has failed.
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Project description:Peposertib (M3814) is a potent and selective DNA-PK inhibitor in early clinical development. It effectively blocks non-homologous end-joining repair of DNA double-strand breaks (DSB) and strongly potentiates the antitumor effect of ionizing radiation (IR) and topoisomerase II inhibitors. By suppressing DNA-PK catalytic activity in the presence of DNA DSB, M3814 potentiates ATM/p53 signaling leading to enhanced p53-dependent antitumor activity in tumor cells. Here, we investigated the therapeutic potential of M3814 in combination with DSB-inducing agents in leukemia cells and a patient-derived tumor. We show that in the presence of IR or topoisomerase II inhibitors, M3814 boosts the ATM/p53 response in acute leukemia cells leading to the elevation of p53 protein levels as well as its transcriptional activity. M3814 synergistically sensitized p53 wild-type, but not p53-deficient, AML cells to killing by DSB-inducing agents via p53-dependent apoptosis involving both intrinsic and extrinsic effector pathways. The antileukemic effect was further potentiated by enhancing daunorubicin-induced myeloid cell differentiation. Further, combined with the fixed-ratio liposomal formulation of daunorubicin and cytarabine, CPX-351, M3814 enhanced the efficacy against leukemia cells in vitro and in vivo without increasing hematopoietic toxicity, suggesting that DNA-PK inhibition could offer a novel clinical strategy for harnessing the anticancer potential of p53 in AML therapy.
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Project description:We have previously identified a recurrent deletion at chromosomal band 3p14.1-p13 in patients with acute myeloid leukemia (AML). Among eight protein-coding genes, this microdeletion affects the protein phosphatase 4 regulatory subunit 2 (PPP4R2), which plays an important role in DNA damage response (DDR). Investigation of mRNA expression during murine myelopoiesis determined that Ppp4r2 is higher expressed in more primitive hematopoietic cells. PPP4R2 expression in primary AML samples compared to healthy bone marrow was significantly lower, particularly in patients with 3p microdeletion or complex karyotype. To identify a functional role of PPP4R2 in hematopoiesis and leukemia, we genetically inactivated Ppp4r2 by RNAi in murine hematopoietic stem and progenitor cells and murine myeloid leukemia. Furthermore, we ectopically expressed PPP4R2 in a deficient human myeloid leukemic cell line. While PPP4R2 is involved in DDR of both hematopoietic and leukemic cells, our findings indicate that PPP4R2 deficiency impairs de-phosphorylation of phosphorylated key DDR proteins KRAB-domain associated protein 1 (pKAP1), histone variant H2AX (?H2AX), tumor protein P53 (pP53), and replication protein A2 (pRPA2). Potential impact of affected DNA repair processes in primary AML cases with regard to differential PPP4R2 expression or 3p microdeletion is also supported by our results obtained by gene expression profiling and whole exome sequencing. Impaired DDR and increased DNA damage by PPP4R2 suppression is one possible mechanism by which the 3p microdeletion may contribute to the pathogenesis of AML. Further studies are warranted to determine the potential benefit of inefficient DNA repair upon PPP4R2 deletion to the development of therapeutic agents.
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Project description:BackgroundSecondary tumors, including therapy-related acute myeloid leukemia (t-AML), represent one of the most undesirable side effects of chemotherapy, which arise several years after primary cancer treatment. This review aims to analyze the current data on molecular pathogenesis of t-AML revealing potential criteria for predicting predisposition to the disease. Another objective is to analyze the information on promising approaches for t-AML prevention.MethodsWe analyzed studies regarding t-AML and possible approaches for cancer prevention of drug-induced tumors. Publications in the databases, such as SciVerse Scopus (948), PubMed (1837) and Web of Science (935) were used. Among 92 the most important publications cited in the review, 79 were published during the last decade.ResultsThe review provides the information concerning t-AML pathogenesis, molecular markers of primary cancer patients with high risk of t-AML. The role of the bone marrow niche in clonal hematopoiesis and t-AML pathogenesis is discussed. Current approaches for t-AML prevention both at the stage of therapy and at the latent period are described. Inhibition effects of polyphenols on cell proliferation and on the appearance of hemopoetic clones of indeterminate potential are proposed for t-AML prevention.ConclusionThe problem of the t-AML, a cancer induced by genotoxic chemotherapeutic drugs, is considered from the point of view of the fundamental mechanisms of chemical carcinogenesis, highlighting initiation and promotion stages. It enables to reveal the possible markers for the group of patients with high risk for t-AML and to demonstrate perspectives for the use of plant polyphenols for t-AML prevention.
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Project description: Not available
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Project description:Late relapse, defined as relapse arising after at least 5 years of remission, is rare and occurs in 1-3% of patients with acute myeloid leukemia (AML). The underlying mechanisms of late relapse remain poorly understood. We identified patients with AML who achieved remission with standard induction chemotherapy and relapsed after at least five years of remission (n = 15). Whole exome sequencing was performed in available bone marrow samples obtained at diagnosis (n = 10), remission (n = 6), and first relapse (n = 10). A total of 41 driver mutations were identified, of which 11 were primary tumor-specific, 17 relapse-specific, and 13 shared (detected both in primary and relapsed tumor samples). We demonstrated that 12 of 13 shared mutations were in epigenetic modifier and spliceosome genes. Longitudinal genomic characterization revealed that in eight of 10 patients the founder leukemic clone persisted after chemotherapy and established the basis of relapse years later. Understanding the mechanisms of such quiescence in leukemic cells may help designing future strategies aimed at increasing remission duration in patients with AML.
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