title: Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome.
abstract: Somatic mutations in spliceosome genes are detectable in ∼50% of patients with myelodysplastic syndromes (MDS). We hypothesize that cells harbouring spliceosome gene mutations have increased sensitivity to pharmacological perturbation of the spliceosome. We focus on mutant U2AF1 and utilize sudemycin compounds that modulate pre-mRNA splicing. We find that haematopoietic cells expressing mutant U2AF1(S34F), including primary patient cells, have an increased sensitivity to in vitro sudemycin treatment relative to controls. In vivo sudemycin treatment of U2AF1(S34F) transgenic mice alters splicing and reverts haematopoietic progenitor cell expansion induced by mutant U2AF1 expression. The splicing effects of sudemycin and U2AF1(S34F) can be cumulative in cells exposed to both perturbations-drug and mutation-compared with cells exposed to either alone. These cumulative effects may result in downstream phenotypic consequences in sudemycin-treated mutant cells. Taken together, these data suggest a potential for treating haematological cancers harbouring U2AF1 mutations with pre-mRNA splicing modulators like sudemycins.
authors.affiliation: Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Cara Lunn
authors.initials: CL
authors.lastname: Shirai
authors.affiliation: Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Brian S
authors.identifier: 0000-0002-2954-4410
authors.initials: BS
authors.lastname: White
authors.affiliation: Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Manorama
authors.initials: M
authors.lastname: Tripathi
authors.affiliation: Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Tapia
authors.affiliation: Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: James N
authors.initials: JN
authors.lastname: Ley
authors.affiliation: Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ndonwi
authors.affiliation: Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Sanghyun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Shao
authors.affiliation: Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Alexa
authors.initials: A
authors.lastname: Carver
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
authors.forename: Borja
authors.initials: B
authors.lastname: Saez
authors.affiliation: McDonnell Genome Institute, Washington University, St Louis, Missouri 63108, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.affiliation: McDonnell Genome Institute, Washington University, St Louis, Missouri 63108, USA.
authors.forename: Catrina
authors.initials: C
authors.lastname: Fronick
authors.affiliation: McDonnell Genome Institute, Washington University, St Louis, Missouri 63108, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: O'Laughlin
authors.affiliation: SRI International, Bioscience Division, Menlo Park, California 94025, USA.
authors.forename: Chandraiah
authors.initials: C
authors.lastname: Lagisetti
authors.affiliation: SRI International, Bioscience Division, Menlo Park, California 94025, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Webb
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
authors.affiliation: Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Matthew J
authors.identifier: 0000-0002-7753-1091
authors.initials: MJ
authors.lastname: Walter
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003514:Cyclohexylamines / Q000494:pharmacology*; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D012326:RNA Splicing / Q000187:drug effects*; D013141:Spiro Compounds / Q000494:pharmacology*; D017381:Spliceosomes / Q000187:drug effects* / Q000235:genetics; D000072668:Splicing Factor U2AF / Q000235:genetics* / Q000378:metabolism
chemical_list: C586721:5-((4-(5-(7,7-dimethyl-1,6-dioxaspiro(2.5)octan-5-yl)-3-methylpenta-2,4-dien-1-yl)cyclohexyl)amino)-5-oxopent-3-en-2-yl methylcarbamate; D003514:Cyclohexylamines; D013141:Spiro Compounds; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human