Therapeutic targeting of RNA splicing in myelodysplasia Journal Article


Authors: Kim, Y. J.; Abdel-Wahab, O.
Article Title: Therapeutic targeting of RNA splicing in myelodysplasia
Abstract: Genomic analysis of patients with myelodysplastic syndromes (MDS) has identified that mutations within genes encoding RNA splicing factors represent the most common class of genetic alterations in MDS. These mutations primarily affect SF3B1, SRSF2, U2AF1, and ZRSR2. Current data suggest that these mutations perturb RNA splicing catalysis in a manner distinct from loss of function but how exactly the global changes in RNA splicing imparted by these mutations result in MDS is not well delineated. At the same time, cells bearing mutations in RNA splicing factors are exquisitely dependent on the presence of the remaining wild-type (WT) allele to maintain residual normal splicing for cell survival. The high frequency of these mutations in MDS, combined with their mutual exclusivity and noteworthy dependence on the WT allele, make targeting RNA splicing attractive in MDS. To this end, two promising therapeutic approaches targeting RNA splicing are being tested clinically currently. These include molecules targeting core RNA splicing catalysis by interfering with the ability of the SF3b complex to interact with RNA, as well as molecules degrading the auxiliary RNA splicing factor RBM39. The preclinical and clinical evaluation of these compounds are discussed here in addition to their potential as therapies for spliceosomal mutant MDS. © 2017 Elsevier Inc.
Keywords: unclassified drug; gene mutation; pathogenesis; review; nonhuman; drug targeting; genetic analysis; allele; cell survival; wild type; rna binding protein; hematologic malignancy; myelodysplastic syndrome; drug mechanism; sulfonamide; catalysis; spliceosome; indisulam; epithelium tumor; rna splicing; myelodysplastic syndromes; mutant; splicing; human; priority journal; sf3b1; srsf2; u2af1; 5 chlorosulfaquinoxaline; protein rbm39
Journal Title: Seminars in Hematology
Volume: 54
Issue: 3
ISSN: 0037-1963
Publisher: W.B. Saunders Co-Elsevier Inc.  
Date Published: 2017-07-01
Start Page: 167
End Page: 173
Language: English
DOI: 10.1053/j.seminhematol.2017.06.007
PROVIDER: scopus
PUBMED: 28958291
DOI/URL:
Notes: Review -- Export Date: 1 December 2017 -- Source: Scopus
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MSK Authors
  1. Young Joon Joon Kim
    2 Kim