title: Targeting Splicing in the Treatment of Myelodysplastic Syndromes and Other Myeloid Neoplasms.
abstract: Genome sequencing of primary cells from patients with myelodysplastic syndromes (MDS) led to the identification of recurrent heterozygous mutations in gene encoding components of the spliceosome, the cellular machinery which processes pre-messenger RNA (mRNA) to mature mRNA during gene transcription. Splicing mutations are mutually exclusive with one another and collectively represent the most common mutation class in MDS, occurring in approximately 60 % of patients overall and more than 80 % of those with ring sideroblasts. Evidence from animal models suggests that homozygous splicing mutations are lethal, and that in heterozygously mutated models, any further disruption of splicing triggers apoptosis and cell death. MDS cells with spliceosome mutations are thus uniquely vulnerable to therapies targeting splicing, which may be tolerated by healthy cells. The spliceosome is emerging as a novel therapeutic target in MDS and related myeloid neoplasms, with the first clinical trial of a splicing modulator opening in 2016.
authors: Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK.
authors: Charlotte K
authors: CK
authors: Brierley
authors: Adult Leukemia Program, Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, D2037, 450 Brookline Ave, Boston, MA, 02215, USA. David_Steensma@DFCI.HARVARD.EDU.|Harvard Medical School, 25 Shattuck St, Boston, MA, 02115, USA. David_Steensma@DFCI.HARVARD.EDU.
authors: David P
authors: DP
authors: Steensma
mesh_terms: D000818:Animals; D004852:Epoxy Compounds / Q000627:therapeutic use; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D018942:Macrolides / Q000627:therapeutic use; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics; D000072260:RNA Splicing Factors / Q000235:genetics / Q000378:metabolism; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017381:Spliceosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: C557411:E 7107; D004852:Epoxy Compounds; D007211:Indoles; D018942:Macrolides; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear
keywords: E7107; Myelodysplastic syndromes; SF3B1; Splicing; Targeted therapy