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

Cuijuan Han, Alireza Khodadadi-Jamayran, Adam H. Lorch, Qi Jin, Valentina Serafin, Ping Zhu, Yuliya Politanska, Limin Sun, Blanca T. Gutierrez-Diaz, Marina V. Pryzhkova, Hiam Abdala-Valencia, Elizabeth Thomas Bartom, Barbara Buldini, Giuseppe Basso, Sadanandan E. Velu, Kavitha Sarma, Basil B. Mattamana, Byoung Kyu Cho, Rebecca C. Obeng, Young Ah GooPhilip W. Jordan, Aristotelis Tsirigos, Yalu Zhou, Panagiotis Ntziachristos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article numbereabj8357
JournalScience Advances
Volume8
Issue number3
DOIs
StatePublished - Jan 2022

ASJC Scopus subject areas

  • General

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