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Mutations in spliceosome genes and therapeutic opportunities in myeloid malignancies.

ABSTRACT: Since the discovery of RNA splicing more than 40?years ago, our comprehension of the molecular events orchestrating constitutive and alternative splicing has greatly improved. Dysregulation of pre-mRNA splicing has been observed in many human diseases including neurodegenerative diseases and cancer. The recent identification of frequent somatic mutations in core components of the spliceosome in myeloid malignancies and functional analysis using model systems has advanced our knowledge of how splicing alterations contribute to disease pathogenesis. In this review, we summarize our current understanding on the mechanisms of how mutant splicing factors impact splicing and the resulting functional and pathophysiological consequences. We also review recent advances to develop novel therapeutic approaches targeting splicing catalysis and splicing regulatory proteins, and discuss emerging technologies using oligonucleotide-based therapies to modulate pathogenically spliced isoforms.

SUBMITTER: Taylor J

PROVIDER: S-EPMC6852509 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Mutations in spliceosome genes and therapeutic opportunities in myeloid malignancies.

Taylor Justin J Lee Stanley C SC

Genes, chromosomes & cancer 20190903 12

Since the discovery of RNA splicing more than 40 years ago, our comprehension of the molecular events orchestrating constitutive and alternative splicing has greatly improved. Dysregulation of pre-mRNA splicing has been observed in many human diseases including neurodegenerative diseases and cancer. The recent identification of frequent somatic mutations in core components of the spliceosome in myeloid malignancies and functional analysis using model systems has advanced our knowledge of how spl ...[more]

PMID: 31334570

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Project description:Alterations to genes involved in cellular metabolism and epigenetic regulation are implicated in the pathogenesis of myeloid malignancies. Recurring mutations in isocitrate dehydrogenase (IDH) genes are detected in approximately 20% of adult patients with acute myeloid leukemia (AML) and 5% of adults with myelodysplastic syndromes (MDS). IDH proteins are homodimeric enzymes involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation and DNA modification. The IDH2 protein is localized in the mitochondria and is a critical component of the tricarboxylic acid (also called the 'citric acid' or Krebs) cycle. Both IDH2 and IDH1 (localized in the cytoplasm) proteins catalyze the oxidative decarboxylation of isocitrate to ?-ketoglutarate (?-KG). Mutant IDH enzymes have neomorphic activity and catalyze reduction of ?-KG to the (R) enantiomer of 2-hydroxyglutarate, which is associated with DNA and histone hypermethylation, altered gene expression and blocked differentiation of hematopoietic progenitor cells. The prognostic significance of mutant IDH (mIDH) is controversial but appears to be influenced by co-mutational status and the specific location of the mutation (IDH1-R132, IDH2-R140, IDH2-R172). Treatments specifically or indirectly targeted to mIDH are currently under clinical investigation; these therapies have been generally well tolerated and, when used as single agents, have shown promise for inducing responses in some mIDH patients when used as first-line treatment or in relapsed or refractory AML or MDS. Use of mIDH inhibitors in combination with drugs with non-overlapping mechanisms of action is especially promising, as such regimens may address the clonal heterogeneity and the multifactorial pathogenic processes involved in mIDH myeloid malignancies. Advances in mutational analysis have made testing more rapid and convenient, and less expensive; such testing should become part of routine diagnostic workup and repeated at relapse to identify patients who may benefit from treatments that target mIDH.

Dataset Information

Mutations in spliceosome genes and therapeutic opportunities in myeloid malignancies.

Publications

Mutations in spliceosome genes and therapeutic opportunities in myeloid malignancies.

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