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Ref Type Journal Article
PMID (28067246)
Authors Shirai CL, White BS, Tripathi M, Tapia R, Ley JN, Ndonwi M, Kim S, Shao J, Carver A, Saez B, Fulton RS, Fronick C, O'Laughlin M, Lagisetti C, Webb TR, Graubert TA, Walter MJ
Title Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome.
Journal Vol Issue Date Pages Journal Short Title
Nature communications 8 2017 01 09 14060 Nat Commun
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Sudemycin D1 Sudemycin D1 0 0
Sudemycin D6 Sudemycin D6 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
Sudemycin D1 Sudemycin D1 is a synthetic compound that targets spilcesome function, therefore exhibits antitumor activity (PMID: 28067246).
Sudemycin D6 Sudemycin D6 is a synthetic compound that targets spilcesome function, therefore exhibits antitumor activity (PMID: 28067246).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References