Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins Journal Article


Authors: Lee, S. C. W.; Dvinge, H.; Kim, E.; Cho, H.; Micol, J. B.; Chung, Y. R.; Durham, B. H.; Yoshimi, A.; Kim, Y. J.; Thomas, M.; Lobry, C.; Chen, C. W.; Pastore, A.; Taylor, J.; Wang, X.; Krivtsov, A.; Armstrong, S. A.; Palacino, J.; Buonamici, S.; Smith, P. G.; Bradley, R. K.; Abdel-Wahab, O.
Article 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)(1-3). These mutations recurrently affect specific amino acid residues, leading to perturbed normal splice site and exon recognition(4-6). 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.
Keywords: inhibitor; genome; myelodysplastic syndromes; solid tumors; mutations; expression; phase-i; clonal hematopoiesis; rna-seq data; srsf2; e7107
Journal Title: Nature Medicine
Volume: 22
Issue: 6
ISSN: 1078-8956
Publisher: Nature Publishing Group  
Date Published: 2016-06-01
Start Page: 672
End Page: 678
Language: English
ACCESSION: WOS:000377476000025
DOI: 10.1038/nm.4097
PROVIDER: wos
PMCID: PMC4899191
PUBMED: 27135740
Notes: Article -- Source: Wos
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. Young Rock Chung
    48 Chung
  2. Scott Allen Armstrong
    108 Armstrong
  3. Chun-Wei Chen
    20 Chen
  4. Xujun Wang
    3 Wang
  5. Eunhee Kim
    29 Kim
  6. Jean- Baptiste Micol
    23 Micol
  7. Stanley Chun-Wei Lee
    43 Lee
  8. Benjamin Heath Durham
    117 Durham
  9. Hana Cho
    21 Cho
  10. Alessandro   Pastore
    55 Pastore
  11. Akihide   Yoshimi
    35 Yoshimi
  12. Young Joon Joon Kim
    2 Kim
  13. Justin   Taylor
    51 Taylor