Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins
| Autor: | Heidi Dvinge, James Palacino, Robert K. Bradley, Chun-Wei Chen, Xujun Wang, Justin Taylor, Pete Smith, Alessandro Pastore, Jean-Baptiste Micol, Scott A. Armstrong, Benjamin H. Durham, Michael P. Thomas, Eunhee Kim, Camille Lobry, Silvia Buonamici, Stanley Chun-Wei Lee, Young Joon Kim, Young Rock Chung, Omar Abdel-Wahab, Akihide Yoshimi, Andrei V. Krivtsov, Hana Cho |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Spliceosome RNA Splicing Hemoglobinuria Paroxysmal Biology medicine.disease_cause Catalysis Article General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences Exon Cell Line Tumor hemic and lymphatic diseases medicine Animals Humans Gene Knock-In Techniques Bone Marrow Diseases Bone Marrow Transplantation Hemizygote Mice Knockout Genetics Mutation Serine-Arginine Splicing Factors Reverse Transcriptase Polymerase Chain Reaction Intron Anemia Aplastic Myeloid leukemia General Medicine Bone Marrow Failure Disorders Flow Cytometry medicine.disease Exon skipping 3. Good health Leukemia Myeloid Acute Leukemia 030104 developmental biology Myelodysplastic Syndromes RNA splicing Spliceosomes Epoxy Compounds Macrolides Neoplasm Transplantation |
| Zdroj: | Nature Medicine. 22:672-678 |
| ISSN: | 1546-170X 1078-8956 |
| DOI: | 10.1038/nm.4097 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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