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

Muvarak, Nidal; Kelley, Shannon; Robert, Carine; Baer, Maria R.; Perrotti, Danilo; Gambacorti‐Passerini, Carlo; Civin, Curt I.; Scheibner, Kara; Rassool, Feyruz V.

doi:10.1158/1541-7786.mcr-14-0422

Cited by 58 publications

(55 citation statements)

References 48 publications

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“…Because this is apparently not the case, there must be some control mechanisms of this self-mutagenesis and its influence on genomic stability. We and others showed that BCR-ABL1 could modulate DNA repair and this modulation was in many cases expressed as an increase in DNA repair efficacy, including efficacy of removing oxidative DNA damage (Slupianek et al, 2013;Muvarak et al, 2015;Nieborowska-Skorska et al, 2006;Somsedikova et al, 2014;Wang et al, 2014, Takagi et al, 2013Brady et al, 2003). Therefore, the modulation of DNA repair by BCR-ABL1 can be associated with the control of ROS-induced self-mutagenesis to adjust it to such level, which would stimulate cancer transformation of CML cells, but below the threshold, which cannot be tolerated by the cell, leading to its apoptosis.…”

Section: Bcr-abl1 and Ros Productionmentioning

confidence: 98%

Reactive oxygen species in BCR-ABL1-expressing cells – relevance to chronic myeloid leukemia

2016

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Chronic myeloid leukemia (CML) results from the t(9;22) reciprocal chromosomal translocation producing the BCR-ABL1 gene, conferring growth and proliferation advantages in the CML cells. CML progresses from chronic, often syndrome-free, to blast phase, fatal if not treated. Although the involvement of BCR-ABL1 in some signaling pathways is considered as the cause of CML, the mechanisms resulting in its progression are not completely known. However, BCR-ABL1 stimulates the production of reactive oxygen species (ROS), which levels increase with CML progression and induce BCR-ABL1 self-mutagenesis. Introducing imatinib and other tyrosine kinase inhibitors (TKIs) to CML therapy radically improved its outcome, but TKIs-resistance became an emerging problem. TKI resistance can be associated with even higher ROS production than in TKI-sensitive cells. Therefore, ROS-induced self-mutagenesis of BCR-ABL1 can be crucial for CML progression and TKI resistance and in this way should be taken into account in therapeutic strategies. As a continuous production of ROS by BCR-ABL1 would lead to its self-destruction and death of CML cells, there must be mechanisms controlling this phenomenon. These can be dependent on DNA repair, which is modulated by BCR-ABL1 and can be different in CML stem and progenitor cells. Altogether, the mechanisms of the involvement of BCR-ABL1 in ROS signaling can be engaged in CML progression and TKI-resistance and warrant further study.

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Section: Bcr-abl1 and Ros Productionmentioning

confidence: 98%

Reactive oxygen species in BCR-ABL1-expressing cells – relevance to chronic myeloid leukemia

2016

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“…MYC has been found overexpressed not only in lymphoma cells but also in chronic myeloid leukemia (CML) patients [59], in ALL patients harboring the translocations t(8;14), t(8;22), and t(2;8) [60] and in AML [61]. In a recent study, Muvarak and colleagues showed that in BCR-ABL1 and FLT3/ITD-positive leukemia cells, the constitutive activation of these kinases, via the overexpression of MYC, triggers intracellular pathways that increase genomic instability through generation of ROS, DSBs, and error-prone repair [62]. A study from Cavelier C. and colleagues showed that in primary AML samples with complex karyotype, the level of DNA damage detected by phospho-H2AX as well as the level of activated CHK1 is higher than in AML samples with normal karyotype and in normal hematopoietic precursors [63].…”

Section: Introductionmentioning

confidence: 99%

The cell cycle checkpoint inhibitors in the treatment of leukemias

2017

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The inhibition of the DNA damage response (DDR) pathway in the treatment of cancers has recently reached an exciting stage with several cell cycle checkpoint inhibitors that are now being tested in several clinical trials in cancer patients. Although the great amount of pre-clinical and clinical data are from the solid tumor experience, only few studies have been done on leukemias using specific cell cycle checkpoint inhibitors. This review aims to summarize the most recent data found on the biological mechanisms of the response to DNA damages highlighting the role of the different elements of the DDR pathway in normal and cancer cells and focusing on the main genetic alteration or aberrant gene expression that has been found on acute and chronic leukemias. This review, for the first time, outlines the most important pre-clinical and clinical data available on the efficacy of cell cycle checkpoint inhibitors in single agent and in combination with different agents normally used for the treatment of acute and chronic leukemias.

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“…proteins have been proposed to active leukemia via transcription error [35]. Our results found that one novel transcript (UniProt identifier: I3L9T2_PIG) of LGI3 have gained a domain (DNA ligase 3 BRCT domain) than the most similar known transcript (UniProt identifier: I3LN18_PIG; Fig.…”

Section: Potential Effect Of Novel Alternative Splicing On the Pig Prmentioning

confidence: 63%

Profiling novel alternative splicing within multiple tissues puts insight into the porcine genome annotation

Feng

Zhao

Zheng

et al. 2019

Preprint

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Background Alternative splicing (AS) is a process that mRNA precursor splices intron to form the mature mRNA. AS plays important roles in contributing to transcriptome and proteome divert. However, to date there is no research about pig AS in genome-wide level by RNA sequencing. Results To characterize the AS in pigs, herein we detected genome-wide transcripts and events by RNA sequencing technology (RNA-seq) 34 different tissues in Duroc pigs. In total, we identified 138, 403 AS events and 29, 270 expressed genes. We found alternative donor site was the most common AS form, which is accounted for 44% of the total AS events. The percentage of the other 3 AS forms (Exon skipping, Alternative acceptor site and Intron retention) are all around 19%. The results showed that the most common AS events (alternative donor site) can produce different transcripts or different proteins which affect the biological process. Among these AS events, 109, 483 were novel AS events, and the number of alternative donor splice site has increased the most (Accounting for 44% of the novel AS events). Conclusions The expression of gene with tissue specific AS events showed that the functions of these genes were consistent with the tissue function. AS increased proteome diversity and resulted in novel proteins that gained and lost important functional domains. In summary, these findings extend genome annotation and highlight roles that AS acts in tissue identity in pig.

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

Cited by 58 publications

References 48 publications

Reactive oxygen species in BCR-ABL1-expressing cells – relevance to chronic myeloid leukemia

Reactive oxygen species in BCR-ABL1-expressing cells – relevance to chronic myeloid leukemia

The cell cycle checkpoint inhibitors in the treatment of leukemias

Profiling novel alternative splicing within multiple tissues puts insight into the porcine genome annotation

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