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

Autor: Han C; Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA.; Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Khodadadi-Jamayran A; Applied Bioinformatics Laboratories, Office of Science and Research, New York University School of Medicine, New York, NY, USA., Lorch AH; Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA.; Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Jin Q; Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA.; Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Serafin V; Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Maternal and Child Health Department, Padua University, Padova, Italy., Zhu P; H3 Biomedicine Inc., Cambridge, MA, USA., Politanska Y; Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Sun L; Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA.; Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Gutierrez-Diaz BT; Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA.; Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Pryzhkova MV; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA., Abdala-Valencia H; Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Bartom ET; Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA.; Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Buldini B; Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Maternal and Child Health Department, Padua University, Padova, Italy., Basso G; Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Maternal and Child Health Department, Padua University, Padova, Italy., Velu SE; Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL, USA., Sarma K; Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, USA.; Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA., Mattamana BB; Proteomics Center of Excellence, Northwestern University, Evanston, IL, USA., Cho BK; Proteomics Center of Excellence, Northwestern University, Evanston, IL, USA., Obeng RC; Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA., Goo YA; Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA.; Proteomics Center of Excellence, Northwestern University, Evanston, IL, USA., Jordan PW; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA., Tsirigos A; Applied Bioinformatics Laboratories, Office of Science and Research, New York University School of Medicine, New York, NY, USA.; Department of Pathology and Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA.; Institute for Computational Medicine, NYU School of Medicine, New York, NY, USA., Zhou Y; Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA.; Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Ntziachristos P; Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA.; Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2022 Jan 21; Vol. 8 (3), pp. eabj8357. Date of Electronic Publication: 2022 Jan 21.
DOI: 10.1126/sciadv.abj8357
Abstrakt: 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.
Databáze: MEDLINE