c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase-Activated Leukemias

被引:57
作者
Muvarak, Nidal [1 ,2 ]
Kelley, Shannon [3 ,4 ]
Robert, Carine [1 ,2 ]
Baer, Maria R. [2 ,5 ]
Perrotti, Danilo [2 ,5 ,6 ]
Gambacorti-Passerini, Carlo [7 ]
Civin, Curt [3 ,4 ]
Scheibner, Kara [3 ,4 ]
Rassool, Feyruz V. [1 ,2 ]
机构
[1] Univ Maryland, Sch Med, Dept Radiat Oncol, Baltimore, MD 21201 USA
[2] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA
[3] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA
[4] Univ Maryland, Sch Med, Ctr Stem Cell Biol & Regenerat Med, Baltimore, MD 21201 USA
[5] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA
[6] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Haematol, London, England
[7] Univ Milano Bicocca, Monza, Italy
关键词
CHRONIC MYELOID-LEUKEMIA; DOUBLE-STRAND BREAKS; GENE-EXPRESSION; GENOMIC INSTABILITY; BCR-ABL; CELLS; CANCER; REPRESSION; PATHWAYS; CONSEQUENCES;
D O I
10.1158/1541-7786.MCR-14-0422
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 IIIa (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. Implications: 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.
引用
收藏
页码:699 / 712
页数:14
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