@article{df20d2e5dfad4602aa04cba2da06e2a9,
title = "Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia",
abstract = "Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the β-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/β-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/β-catenin interaction.",
author = "{Van Thillo}, Quentin and {De Bie}, Jolien and Seneviratne, {Janith A.} and Sofie Demeyer and Sofia Omari and Anushree Balachandran and Vicki Zhai and Tam, {Wai L.} and Bram Sweron and Ellen Geerdens and Olga Gielen and Sarah Provost and Heidi Segers and Nancy Boeckx and Marshall, {Glenn M.} and Cheung, {Belamy B.} and Kiyotaka Isobe and Itaru Kato and Junko Takita and Amos, {Timothy G.} and Deveson, {Ira W.} and Hannah McCalmont and Lock, {Richard B.} and Oxley, {Ethan P.} and Garwood, {Maximilian M.} and Dickins, {Ross A.} and Anne Uyttebroeck and Carter, {Daniel R.} and Jan Cools and {de Bock}, {Charles E.}",
note = "Funding Information: This study was supported by a fellowship from the FWO-Vlaanderen (J.D.), Cancer Institute New South Wales (D.R.C.), Children{\textquoteright}s Cancer Institute (C.D.B.), Steven Walter Children{\textquoteright}s Cancer Foundation (A.B.), and by grants from the European Research Council (J.C.), FWO-Vlaanderen (J.C.) and the Foundation against Cancer (J.C.). We would like to thank Prof. Dr. Johannes Zuber, IMP—Research Institute of Molecular Pathology GmbH, Austria for providing the LT3GECIR lentiviral miR-E shRNA vector. We would like to thank the St. Jude Biorepository for providing the two SJTALL03263_D1 and SJTALL031201_D1 TCF7-SPI1 fusion case samples. We thank Dr. Emma Johansson Beves from the Flow Cytometry Facility, Mark Wainwright Analytical Centre at UNSW, Sydney for assistance with flow cytometry and sorting experiments. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = dec,
doi = "10.1038/s41467-021-24442-9",
language = "English",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}