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 Goo; Philip W. Jordan; Aristotelis Tsirigos; Yalu Zhou; Panagiotis Ntziachristos

doi:10.1126/sciadv.abj8357

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 journal › Article › peer-review

21 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 language	English (US)
Article number	eabj8357
Journal	Science Advances
Volume	8
Issue number	3
DOIs	https://doi.org/10.1126/sciadv.abj8357
State	Published - Jan 2022

Funding

The Ntziachristos laboratory is or has been supported by the NCI (R00CA188293 and R01CA248770), the National Science Foundation, the Hartwell Foundation, a Gilead Research Scholarship, the American Society of Hematology, the Leukemia Research Foundation, the St. Baldrick's Foundation, the H Foundation, the Gabrielle's Angel Foundation, the Elsa Pardee Foundation, the Zell Foundation, and an Odysseus Grant from Research Foundation Flanders (FWO, G0F4721N). A.T. is supported by the American Cancer Society (RSG-15-189-01-RMC), St. Baldrick's Foundation (581357), NCI/NIH P01CA229086, and NCI/NIH R01CA252239. We would also like to thank the Applied Bioinformatics Laboratories (ABL) for providing bioinformatics support and helping with the analysis and interpretation of the data. ABL are supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. This work has used computing resources at the NYU School of Medicine High Performance Computing Facility. V.S. is supported by Fondazione Associazione Italiana per la Ricerca sul Cancro (AIRC, MFAG 2018, ID. 21771). K.S. is supported by the NIH (DP2-NS105576). E.T.B. was supported by NCI, 5R50CA221848-04. Genomics services were performed by the Metabolomics Core Facility (Integrative Genomics Branch) at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Histology services were provided by the Northwestern University Research Mouse Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center.

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Han, C., Khodadadi-Jamayran, A., Lorch, A. H., Jin, Q., Serafin, V., Zhu, P., Politanska, Y., Sun, L., Gutierrez-Diaz, B. T., Pryzhkova, M. V., Abdala-Valencia, H., Bartom, E. T., Buldini, B., Basso, G., Velu, S. E., Sarma, K., Mattamana, B. B., Cho, B. K., Obeng, R. C., ... Ntziachristos, P. (2022). SF3B1 homeostasis is critical for survival and therapeutic response in T cell leukemia. Science Advances, 8(3), Article eabj8357. https://doi.org/10.1126/sciadv.abj8357

@article{f87ce25a1b4f48bc9cb56564e89babd8,

title = "SF3B1 homeostasis is critical for survival and therapeutic response in T cell leukemia",

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.",

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

note = "Funding Information: The Ntziachristos laboratory is or has been supported by the NCI (R00CA188293 and R01CA248770), the National Science Foundation, the Hartwell Foundation, a Gilead Research Scholarship, the American Society of Hematology, the Leukemia Research Foundation, the St. Baldrick's Foundation, the H Foundation, the Gabrielle's Angel Foundation, the Elsa Pardee Foundation, the Zell Foundation, and an Odysseus Grant from Research Foundation Flanders (FWO, G0F4721N). A.T. is supported by the American Cancer Society (RSG-15-189-01-RMC), St. Baldrick's Foundation (581357), NCI/NIH P01CA229086, and NCI/NIH R01CA252239. We would also like to thank the Applied Bioinformatics Laboratories (ABL) for providing bioinformatics support and helping with the analysis and interpretation of the data. ABL are supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. This work has used computing resources at the NYU School of Medicine High Performance Computing Facility. V.S. is supported by Fondazione Associazione Italiana per la Ricerca sul Cancro (AIRC, MFAG 2018, ID. 21771). K.S. is supported by the NIH (DP2-NS105576). E.T.B. was supported by NCI, 5R50CA221848-04. Genomics services were performed by the Metabolomics Core Facility (Integrative Genomics Branch) at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Histology services were provided by the Northwestern University Research Mouse Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).",

year = "2022",

month = jan,

doi = "10.1126/sciadv.abj8357",

language = "English (US)",

volume = "8",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "3",

}

Han, C, Khodadadi-Jamayran, A, Lorch, AH, Jin, Q, Serafin, V, Zhu, P, Politanska, Y, Sun, L, Gutierrez-Diaz, BT, Pryzhkova, MV, Abdala-Valencia, H , Bartom, ET, Buldini, B, Basso, G, Velu, SE, Sarma, K, Mattamana, BB, Cho, BK, Obeng, RC, Goo, YA, Jordan, PW, Tsirigos, A, Zhou, Y & Ntziachristos, P 2022, 'SF3B1 homeostasis is critical for survival and therapeutic response in T cell leukemia', Science Advances, vol. 8, no. 3, eabj8357. https://doi.org/10.1126/sciadv.abj8357

TY - JOUR

T1 - SF3B1 homeostasis is critical for survival and therapeutic response in T cell leukemia

AU - Han, Cuijuan

AU - Khodadadi-Jamayran, Alireza

AU - Lorch, Adam H.

AU - Jin, Qi

AU - Serafin, Valentina

AU - Zhu, Ping

AU - Politanska, Yuliya

AU - Sun, Limin

AU - Gutierrez-Diaz, Blanca T.

AU - Pryzhkova, Marina V.

AU - Abdala-Valencia, Hiam

AU - Bartom, Elizabeth Thomas

AU - Buldini, Barbara

AU - Basso, Giuseppe

AU - Velu, Sadanandan E.

AU - Sarma, Kavitha

AU - Mattamana, Basil B.

AU - Cho, Byoung Kyu

AU - Obeng, Rebecca C.

AU - Goo, Young Ah

AU - Jordan, Philip W.

AU - Tsirigos, Aristotelis

AU - Zhou, Yalu

AU - Ntziachristos, Panagiotis

N1 - Funding Information: The Ntziachristos laboratory is or has been supported by the NCI (R00CA188293 and R01CA248770), the National Science Foundation, the Hartwell Foundation, a Gilead Research Scholarship, the American Society of Hematology, the Leukemia Research Foundation, the St. Baldrick's Foundation, the H Foundation, the Gabrielle's Angel Foundation, the Elsa Pardee Foundation, the Zell Foundation, and an Odysseus Grant from Research Foundation Flanders (FWO, G0F4721N). A.T. is supported by the American Cancer Society (RSG-15-189-01-RMC), St. Baldrick's Foundation (581357), NCI/NIH P01CA229086, and NCI/NIH R01CA252239. We would also like to thank the Applied Bioinformatics Laboratories (ABL) for providing bioinformatics support and helping with the analysis and interpretation of the data. ABL are supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. This work has used computing resources at the NYU School of Medicine High Performance Computing Facility. V.S. is supported by Fondazione Associazione Italiana per la Ricerca sul Cancro (AIRC, MFAG 2018, ID. 21771). K.S. is supported by the NIH (DP2-NS105576). E.T.B. was supported by NCI, 5R50CA221848-04. Genomics services were performed by the Metabolomics Core Facility (Integrative Genomics Branch) at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Histology services were provided by the Northwestern University Research Mouse Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Publisher Copyright: Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

PY - 2022/1

Y1 - 2022/1

N2 - 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.

AB - 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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ER -

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

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