Functional role of alternatively spliced deoxycytidine kinase in sensitivity to cytarabine of acute myeloid leukemic cells

Veuger, Marjan J. T.; Heemskerk, Mirjam H.M.; Honders, M. Willy; Willemze, R.; Barge, Renée M. Y.

doi:10.1182/blood.v99.4.1373

Cited by 63 publications

(49 citation statements)

References 31 publications

(31 reference statements)

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“…153,154 Alternatively, inactivation of dCK by the formation of alternatively spliced dCK transcripts has been demonstrated in seven out of 12 patients with resistant AML compared to one out of 10 patients with sensitive AML. 155 This mechanism is probably a cause of therapy failure in patients with resistant AML. 156 Finally, high 5NT expression in blast cells was shown to be an independent prognostic factor for poor outcome in 108 AML patients after ara-Ccontaining regimens.…”

Section: Jg Maring Et Almentioning

confidence: 99%

“…155 This mechanism is probably a cause of therapy failure in patients with resistant AML. 156 Finally, high 5NT expression in blast cells was shown to be an independent prognostic factor for poor outcome in 108 AML patients after ara-Ccontaining regimens. 157 The balance between dCK and 5NT might predict drug toxicity, since strongly increased 5NT activity combined with reduced dCK activity was observed in a human leukaemic cell line, resistant to ara-C and dFdC.…”

Section: Jg Maring Et Almentioning

confidence: 99%

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Genetic factors influencing Pyrimidine-antagonist chemotherapy

et al. 2005

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Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumourspecific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5 0 -nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.

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Section: Jg Maring Et Almentioning

confidence: 99%

Section: Jg Maring Et Almentioning

confidence: 99%

Genetic factors influencing Pyrimidine-antagonist chemotherapy

et al. 2005

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“…Low expression or activity of deoxycytidine kinase (dCK) is responsible for the in vitro cellular resistance to Ara-C in AML cells. Only wildtype mRNA of dCK is amplified from healthy control samples, while splicing variants translating inactive dCK protein resulting from exon skipping are detected in 7 out of 12 purified AML specimen from resistant patients (79). Further work indicates that the alternatively spliced dCK forms render the AML cells to evade to Ara-C attack when there is no wide type dCK (80).…”

Section: Abnormally Spliced (As) Mrnas In Amlmentioning

confidence: 99%

“…Only wildtype mRNA of dCK is amplified from healthy control samples, while splicing variants translating inactive dCK protein resulting from exon skipping are detected in 7 out of 12 purified AML specimen from resistant patients (79). Further work indicates that the alternatively spliced dCK forms render the AML cells to evade to Ara-C attack when there is no wide type dCK (80). On the other side of the coin, exon-array analysis has been performed in isogenic sensitive and (secondary) resistant AML cell lines to Ara-C, doxorubicin (Dox) and hypomethylating agent, azacitidine (Aza) and produced novel insight of alternative exon usages (AEUs) globally (81).…”

Section: Abnormally Spliced (As) Mrnas In Amlmentioning

confidence: 99%

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

Zhou

Chng

2017

Stem Cell Investig.

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The spliceosome, the cellular splicing machinery, regulates RNA splicing of messenger RNA precursors (pre-mRNAs) into maturation of protein coding RNAs. Recurrent mutations and copy number changes in genes encoding spliceosomal proteins and splicing regulatory factors have tumor promoting or suppressive functions in hematological malignancies, as well as some other cancers. Leukemia stem cell (LSC) populations, although rare, are essential contributors of treatment failure and relapse. Recent researches have provided the compelling evidence that link the erratic spicing activity to the LSC phenotype in acute myeloid leukemia (AML). In this article, we describe the diverse roles of aberrant splicing in hematological malignancies, particularly in AML and their contributions to the characteristics of LSC. We review these promising strategies to exploit the addiction of aberrant spliceosomal machinery for anti-leukemic therapy with aim to eradicate LSC. However, given the complexity and plasticity of spliceosome and not fully known functions of splicing in cancer, the challenges facing the development of the therapeutic strategies targeting RAN splicing are highlighted and future directions are discussed too.

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“…There is much interest in finding which genes are showing alternative splicing, analyzing the tissue specificity of alternative splice forms, and identifying the resulting protein isoforms. Evidence that alternative splicing might have an impact on drug efficacy or toxicity (28) in chemotherapy has made alternative splice variants potential drug targets (27,29). Tissue-specific mRNA variants can also act as regulatory RNAs that influence expression of other genes.…”

Section: Alternative Splicingmentioning

confidence: 99%

Using bioinformatics and genome analysis for new therapeutic interventions

Mount

Pandey

2005

Molecular Cancer Therapeutics

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The genome era provides two sources of knowledge to investigators whose goal is to discover new cancer therapies: first, information on the 20,000 to 40,000 genes that comprise the human genome, the proteins they encode, and the variation in these genes and proteins in human populations that place individuals at risk or that occur in disease; second, genome-wide analysis of cancer cells and tissues leads to the identification of new drug targets and the design of new therapeutic interventions.

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Functional role of alternatively spliced deoxycytidine kinase in sensitivity to cytarabine of acute myeloid leukemic cells

Cited by 63 publications

References 31 publications

Genetic factors influencing Pyrimidine-antagonist chemotherapy

Genetic factors influencing Pyrimidine-antagonist chemotherapy

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

Using bioinformatics and genome analysis for new therapeutic interventions

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