title: Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins.
abstract: 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.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Stanley Chun-Wei
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Heidi
authors.identifier: 0000-0003-1741-0738
authors.initials: H
authors.lastname: Dvinge
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Kim
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Hana
authors.initials: H
authors.lastname: Cho
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Micol
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Young Rock
authors.initials: YR
authors.lastname: Chung
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Durham
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Akihide
authors.initials: A
authors.lastname: Yoshimi
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Young Joon
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: H3 Biomedicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Institut National de la Santé et de la Recherche Medicale (INSERM) U1170, Institut Gustave Roussy, Villejuif, France.
authors.forename: Camille
authors.identifier: 0000-0003-0550-4921
authors.initials: C
authors.lastname: Lobry
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Chen
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pastore
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Xujun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Krivtsov
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.affiliation: H3 Biomedicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: James
authors.initials: J
authors.lastname: Palacino
authors.affiliation: H3 Biomedicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Buonamici
authors.affiliation: H3 Biomedicine, Inc., Cambridge, Massachusetts, USA.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Smith
authors.affiliation: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Robert K
authors.identifier: 0000-0002-8046-1063
authors.initials: RK
authors.lastname: Bradley
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
mesh_terms: D000741:Anemia, Aplastic / Q000235:genetics; D000818:Animals; D001855:Bone Marrow Diseases / Q000235:genetics; D000080983:Bone Marrow Failure Disorders; D016026:Bone Marrow Transplantation; D002384:Catalysis; D045744:Cell Line, Tumor; D004852:Epoxy Compounds / Q000494:pharmacology; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D057898:Hemizygote; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009368:Neoplasm Transplantation; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068103:Serine-Arginine Splicing Factors / Q000235:genetics*; D017381:Spliceosomes / Q000235:genetics*
chemical_list: C557411:E 7107; D004852:Epoxy Compounds; D018942:Macrolides; C499372:SRSF2 protein, mouse; D000068103:Serine-Arginine Splicing Factors