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Ref Type Journal Article
PMID (27135740)
Authors Lee SC, Dvinge H, Kim E, Cho H, Micol JB, Chung YR, Durham BH, Yoshimi A, Kim YJ, Thomas M, Lobry C, Chen CW, Pastore A, Taylor J, Wang X, Krivtsov A, Armstrong SA, Palacino J, Buonamici S, Smith PG, Bradley RK, Abdel-Wahab O
Title Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins.
Journal Nature medicine
Vol 22
Issue 6
Date 2016 06
URL
Abstract Text Mutations in genes encoding splicing factors (which we refer to as spliceosomal genes) are commonly found in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These mutations recurrently affect specific amino acid residues, leading to perturbed normal splice site and exon recognition. Spliceosomal gene mutations are always heterozygous and rarely occur together with one another, suggesting that cells may tolerate only a partial deviation from normal splicing activity. To test this hypothesis, we engineered mice to express a mutated allele of serine/arginine-rich splicing factor 2 (Srsf2(P95H))-which commonly occurs in individuals with MDS and AML-in an inducible, hemizygous manner in hematopoietic cells. These mice rapidly succumbed to fatal bone marrow failure, demonstrating that Srsf2-mutated cells depend on the wild-type Srsf2 allele for survival. In the context of leukemia, treatment with the spliceosome inhibitor E7107 (refs. 7,8) resulted in substantial reductions in leukemic burden, specifically in isogenic mouse leukemias and patient-derived xenograft AMLs carrying spliceosomal mutations. Whereas E7107 treatment of mice resulted in widespread intron retention and cassette exon skipping in leukemic cells regardless of Srsf2 genotype, the magnitude of splicing inhibition following E7107 treatment was greater in Srsf2-mutated than in Srsf2-wild-type leukemia, consistent with the differential effect of E7107 on survival. Collectively, these data provide genetic and pharmacologic evidence that leukemias with spliceosomal gene mutations are preferentially susceptible to additional splicing perturbations in vivo as compared to leukemias without such mutations. Modulation of spliceosome function may thus provide a new therapeutic avenue in genetically defined subsets of individuals with MDS or AML.

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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
SRSF2 P95_P96insR insertion unknown SRSF2 P95_P96insR results in the insertion of one amino acid in the Srsf2 protein between amino acids 95 and 96 (UniProt.org). P95_P96insR has been identified in the scientific literature (PMID: 27135740), but has not been biochemically characterized and therefore, its effect on Srf2 protein function is unknown (PubMed, May 2020).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
SRSF2 P95L acute myeloid leukemia predicted - sensitive E7107 Preclinical - Pdx Actionable In a preclinical study, E7107 treatment induced apoptosis and resulted in reduced tumor burden in a patient-derived xenograft (PDX) model of acute myeloid leukemia harboring SRSF2 P95L (PMID: 27135740). 27135740
KMT2A - MLLT3 SRSF2 P95H acute myeloid leukemia sensitive E7107 Preclinical Actionable In a preclinical study, E7107 treatment decreased tumor burden and prolonged survival in an isogenic mouse model of acute myeloid leukemia expressing KMT2A-MLLT3 (reported as MLL-AF9) and SRSF2 P95H, but not in a model expressing KMT2A-MLLT3 and wild-type SRSF2 (PMID: 27135740). 27135740
SRSF2 P95_P96insR acute myeloid leukemia predicted - sensitive E7107 Preclinical - Pdx Actionable In a preclinical study, E7107 treatment induced apoptosis and resulted in reduced tumor burden in a patient-derived xenograft (PDX) model of acute myeloid leukemia harboring SRSF2 P95_P96insR (PMID: 27135740). 27135740