Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Mol Cancer Res
2015 Apr 01;134:699-712. doi: 10.1158/1541-7786.MCR-14-0422.
Show Gene links
Show Anatomy links
c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase-Activated Leukemias.
Muvarak N
,
Kelley S
,
Robert C
,
Baer MR
,
Perrotti D
,
Gambacorti-Passerini C
,
Civin C
,
Scheibner K
,
Rassool FV
.
???displayArticle.abstract???
Leukemias expressing the constitutively activated tyrosine kinases (TK) BCR-ABL1 and FLT3/ITD activate signaling pathways that increase genomic instability through generation of reactive oxygen species (ROS), DNA double-strand breaks (DSB), and error-prone repair. The nonhomologous end-joining (NHEJ) pathway is a major pathway for DSB repair and is highly aberrant in TK-activated leukemias; an alternative form of NHEJ (ALT-NHEJ) predominates, evidenced by increased expression of DNA ligase IIIα (LIG3) and PARP1, increased frequency of large genomic deletions, and repair using DNA sequence microhomologies. This study, for the first time, demonstrates that the TK target c-MYC plays a role in transcriptional activation and subsequent expression of LIG3 and PARP1 and contributes to the increased error-prone repair observed in TK-activated leukemias. c-MYC negatively regulates microRNAs miR-150 and miR-22, which demonstrate an inverse correlation with LIG3 and PARP1 expression in primary and cultured leukemia cells and chronic myelogenous leukemia human patient samples. Notably, inhibition of c-MYC and overexpression of miR-150 and -22 decreases ALT-NHEJ activity. Thus, BCR-ABL1 or FLT3/ITD induces c-MYC expression, leading to genomic instability via augmented expression of ALT-NHEJ repair factors that generate repair errors. In the context of TK-activated leukemias, c-MYC contributes to aberrant DNA repair through downstream targets LIG3 and PARP1, which represent viable and attractive therapeutic targets.
???displayArticle.pubmedLink???
25828893
???displayArticle.pmcLink???PMC4398615 ???displayArticle.link???Mol Cancer Res ???displayArticle.grants???[+]
Agirre,
Down-regulation of hsa-miR-10a in chronic myeloid leukemia CD34+ cells increases USF2-mediated cell growth.
2008, Pubmed
Agirre,
Down-regulation of hsa-miR-10a in chronic myeloid leukemia CD34+ cells increases USF2-mediated cell growth.
2008,
Pubmed
Albajar,
MYC in chronic myeloid leukemia: induction of aberrant DNA synthesis and association with poor response to imatinib.
2011,
Pubmed
Arlinghaus,
The involvement of Bcr in leukemias with the Philadelphia chromosome.
1998,
Pubmed
Boyd,
Coexamination of site-specific transcription factor binding and promoter activity in living cells.
1999,
Pubmed
Byrne,
Mechanisms of oncogenic chromosomal translocations.
2014,
Pubmed
Chang,
Widespread microRNA repression by Myc contributes to tumorigenesis.
2008,
Pubmed
Cramer-Morales,
Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile.
2013,
Pubmed
Dang,
Targeted cancer therapeutics: biosynthetic and energetic pathways characterized by metabolomics and the interplay with key cancer regulatory factors.
2014,
Pubmed
Delgado,
Myc roles in hematopoiesis and leukemia.
2010,
Pubmed
Fan,
Cells expressing FLT3/ITD mutations exhibit elevated repair errors generated through alternative NHEJ pathways: implications for genomic instability and therapy.
2010,
Pubmed
,
Xenbase
Fatica,
MicroRNA-regulated pathways in hematological malignancies: how to avoid cells playing out of tune.
2013,
Pubmed
Geiss,
Direct multiplexed measurement of gene expression with color-coded probe pairs.
2008,
Pubmed
Hartlerode,
Mechanisms of double-strand break repair in somatic mammalian cells.
2009,
Pubmed
Hehlmann,
Treatment of chronic myeloid leukemia when imatinib fails.
2011,
Pubmed
Hentges,
Evolutionary and functional conservation of the DNA non-homologous end-joining protein, XLF/Cernunnos.
2006,
Pubmed
Hähnel,
Targeting components of the alternative NHEJ pathway sensitizes KRAS mutant leukemic cells to chemotherapy.
2014,
Pubmed
Iliakis,
Backup pathways of NHEJ in cells of higher eukaryotes: cell cycle dependence.
2009,
Pubmed
Jabbour,
Long-term outcomes in the second-line treatment of chronic myeloid leukemia: a review of tyrosine kinase inhibitors.
2011,
Pubmed
Khanna,
DNA double-strand breaks: signaling, repair and the cancer connection.
2001,
Pubmed
Kim,
Constitutive Fms-like tyrosine kinase 3 activation results in specific changes in gene expression in myeloid leukaemic cells.
2007,
Pubmed
Li,
Defective nonhomologous end joining blocks B-cell development in FLT3/ITD mice.
2011,
Pubmed
Lieber,
The mechanism of human nonhomologous DNA end joining.
2008,
Pubmed
Lin,
Transcriptional amplification in tumor cells with elevated c-Myc.
2012,
Pubmed
Lovén,
Revisiting global gene expression analysis.
2012,
Pubmed
Lozzio,
Human myeloid cell lines.
1981,
Pubmed
Luoto,
Tumor cell kill by c-MYC depletion: role of MYC-regulated genes that control DNA double-strand break repair.
2010,
Pubmed
Muvarak,
Genomic instability in chronic myeloid leukemia: targets for therapy?
2012,
Pubmed
Nie,
c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells.
2012,
Pubmed
Notari,
A MAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation.
2006,
Pubmed
Nussenzweig,
A backup DNA repair pathway moves to the forefront.
2007,
Pubmed
O'Donnell,
c-Myc-regulated microRNAs modulate E2F1 expression.
2005,
Pubmed
Rassool,
Targeting abnormal DNA double strand break repair in cancer.
2010,
Pubmed
Ricci,
Direct repression of FLIP expression by c-myc is a major determinant of TRAIL sensitivity.
2004,
Pubmed
Sallmyr,
Up-regulation of WRN and DNA ligase IIIalpha in chronic myeloid leukemia: consequences for the repair of DNA double-strand breaks.
2008,
Pubmed
,
Xenbase
Sallmyr,
Genomic instability in myeloid malignancies: increased reactive oxygen species (ROS), DNA double strand breaks (DSBs) and error-prone repair.
2008,
Pubmed
Sander,
MYC stimulates EZH2 expression by repression of its negative regulator miR-26a.
2008,
Pubmed
Santos,
Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.
2010,
Pubmed
Sawyers,
Molecular consequences of the BCR-ABL translocation in chronic myelogenous leukemia.
1993,
Pubmed
Scheibner,
MiR-27a functions as a tumor suppressor in acute leukemia by regulating 14-3-3θ.
2012,
Pubmed
Seedhouse,
DNA repair contributes to the drug-resistant phenotype of primary acute myeloid leukaemia cells with FLT3 internal tandem duplications and is reversed by the FLT3 inhibitor PKC412.
2006,
Pubmed
Slupianek,
BCR/ABL regulates mammalian RecA homologs, resulting in drug resistance.
2001,
Pubmed
Tobin,
Targeting abnormal DNA double-strand break repair in tyrosine kinase inhibitor-resistant chronic myeloid leukemias.
2013,
Pubmed
Vafa,
c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability.
2002,
Pubmed
Wang,
Phosphorylation regulates c-Myc's oncogenic activity in the mammary gland.
2011,
Pubmed
Xie,
Jak2 is involved in c-Myc induction by Bcr-Abl.
2002,
Pubmed
,
Xenbase
Xu,
miR-22 represses cancer progression by inducing cellular senescence.
2011,
Pubmed