2. Academic Validation
  3. SF3B1 homeostasis is critical for survival and therapeutic response in T cell leukemia

SF3B1 homeostasis is critical for survival and therapeutic response in T cell leukemia

  • Sci Adv. 2022 Jan 21;8(3):eabj8357. doi: 10.1126/sciadv.abj8357.
Cuijuan Han 1 2,  Alireza Khodadadi-Jamayran 3,  Adam H Lorch 1 2,  Qi Jin 1 2,  Valentina Serafin 4,  Ping Zhu 5,  Yuliya Politanska 6,  Limin Sun 1 2,  Blanca T Gutierrez-Diaz 1 2,  Marina V Pryzhkova 7,  Hiam Abdala-Valencia 6,  Elizabeth Thomas Bartom 1 2,  Barbara Buldini 4,  Giuseppe Basso 4,  Sadanandan E Velu 8,  Kavitha Sarma 9 10,  Basil B Mattamana 11,  Byoung-Kyu Cho 11,  Rebecca C Obeng 12 13,  Young Ah Goo 1 11,  Philip W Jordan 7,  Aristotelis Tsirigos 3 14 15,  Yalu Zhou 1 2,  Panagiotis Ntziachristos 1 2 13
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA.
  • 2 Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 3 Applied Bioinformatics Laboratories, Office of Science and Research, New York University School of Medicine, New York, NY, USA.
  • 4 Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Maternal and Child Health Department, Padua University, Padova, Italy.
  • 5 H3 Biomedicine Inc., Cambridge, MA, USA.
  • 6 Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 7 Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
  • 8 Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 9 Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, USA.
  • 10 Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA.
  • 11 Proteomics Center of Excellence, Northwestern University, Evanston, IL, USA.
  • 12 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 13 Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.
  • 14 Department of Pathology and Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA.
  • 15 Institute for Computational Medicine, NYU School of Medicine, New York, NY, USA.
PMID: 35061527 DOI: 10.1126/sciadv.abj8357
Abstract

The production of noncanonical mRNA transcripts is associated with cell transformation. Driven by our previous findings on the sensitivity of T cell acute lymphoblastic leukemia (T-ALL) cells to SF3B1 inhibitors, we identified that SF3B1 inhibition blocks T-ALL growth in vivo with no notable associated toxicity. We also revealed protein stabilization of the U2 complex component SF3B1 via deubiquitination. Our studies showed that SF3B1 inhibition perturbs exon skipping, leading to nonsense-mediated decay and diminished levels of DNA damage response-related transcripts, such as the serine/threonine kinase CHEK2, and impaired DNA damage response. We also identified that SF3B1 inhibition leads to a general decrease in R-loop formation. We further demonstrate that clinically used SF3B1 inhibitors synergize with CHEK2 inhibitors and chemotherapeutic drugs to block leukemia growth. Our study provides the proof of principle for posttranslational regulation of splicing components and associated roles and therapeutic implications for the U2 complex in T cell leukemia.

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