title: c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase-Activated Leukemias.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland. Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Nidal
authors.initials: N
authors.lastname: Muvarak
authors.affiliation: Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland. The Center for Stem Cell Biology and Regenerative Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Shannon
authors.initials: S
authors.lastname: Kelley
authors.affiliation: Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland. Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Carine
authors.initials: C
authors.lastname: Robert
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland. Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland. Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland. Department of Haematology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.affiliation: University of Milano-Bicocca Monza, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
authors.affiliation: Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland. The Center for Stem Cell Biology and Regenerative Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Curt
authors.initials: C
authors.lastname: Civin
authors.affiliation: Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland. The Center for Stem Cell Biology and Regenerative Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Kara
authors.initials: K
authors.lastname: Scheibner
authors.affiliation: Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland. Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland. FRassool@som.umaryland.edu.
authors.forename: Feyruz V
authors.initials: FV
authors.lastname: Rassool
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D059766:DNA End-Joining Repair; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics*; D004273:DNA, Neoplasm / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D000075223:Poly-ADP-Ribose Binding Proteins; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D014158:Transcription, Genetic; D029867:Xenopus Proteins
chemical_list: D004273:DNA, Neoplasm; C489427:MYC protein, human; D035683:MicroRNAs; D000075223:Poly-ADP-Ribose Binding Proteins; D016271:Proto-Oncogene Proteins c-myc; D029867:Xenopus Proteins; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011505:Protein-Tyrosine Kinases; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C000618816:DNA ligase III alpha protein, Xenopus; C000618817:LIG3 protein, human; C000618818:Lig3 protein, mouse
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