Oncogenic Cooperation Between TCF7-SPI1 and NRAS(G12D) Requires β-catenin Activity to Drive T-cell Acute Lymphoblastic Leukemia

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Jul 7

PMID 34230493

Citations 8

Authors

Quentin Van Thillo

Jolien De Bie

Janith A Seneviratne

Sofie Demeyer

Sofia Omari

Anushree Balachandran

Vicki Zhai

Wai L Tam

Bram Sweron

Ellen Geerdens

Olga Gielen

Sarah Provost

Heidi Segers

Nancy Boeckx

Glenn M Marshall

Belamy B Cheung

Kiyotaka Isobe

Itaru Kato

Junko Takita

Timothy G Amos

Ira W Deveson

Hannah McCalmont

Richard B Lock

Ethan P Oxley

Maximilian M Garwood

Ross A Dickins

Anne Uyttebroeck

Daniel R Carter

Jan Cools

Charles E de Bock

Affiliations

Soon will be listed here.

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.

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References

Zhu X, Zhang H, Qian M, Zhao X, Yang W, Wang P . The significance of low PU.1 expression in patients with acute promyelocytic leukemia. J Hematol Oncol. 2012; 5:22. PMC: 3407792. DOI: 10.1186/1756-8722-5-22. View

Anderson M, DIAMOND R, Rothenberg E . Precise developmental regulation of Ets family transcription factors during specification and commitment to the T cell lineage. Development. 1999; 126(14):3131-48. DOI: 10.1242/dev.126.14.3131. View

Zappia L, Oshlack A . Clustering trees: a visualization for evaluating clusterings at multiple resolutions. Gigascience. 2018; 7(7). PMC: 6057528. DOI: 10.1093/gigascience/giy083. View

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

Fellmann C, Hoffmann T, Sridhar V, Hopfgartner B, Muhar M, Roth M . An optimized microRNA backbone for effective single-copy RNAi. Cell Rep. 2013; 5(6):1704-13. DOI: 10.1016/j.celrep.2013.11.020. View

Park J, Botting R, Conde C, Popescu D, Lavaert M, Kunz D . A cell atlas of human thymic development defines T cell repertoire formation. Science. 2020; 367(6480). PMC: 7611066. DOI: 10.1126/science.aay3224. View

Weber B, Chi A, Chavez A, Yashiro-Ohtani Y, Yang Q, Shestova O . A critical role for TCF-1 in T-lineage specification and differentiation. Nature. 2011; 476(7358):63-8. PMC: 3156435. DOI: 10.1038/nature10279. View

Li Y, Buijs-Gladdines J, Cante-Barrett K, Stubbs A, Vroegindeweij E, Smits W . IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study. PLoS Med. 2016; 13(12):e1002200. PMC: 5172551. DOI: 10.1371/journal.pmed.1002200. View

Herrmann C, Van de Sande B, Potier D, Aerts S . i-cisTarget: an integrative genomics method for the prediction of regulatory features and cis-regulatory modules. Nucleic Acids Res. 2012; 40(15):e114. PMC: 3424583. DOI: 10.1093/nar/gks543. View

10.

van de Wetering M, Oosterwegel M, Holstege F, Dooyes D, Suijkerbuijk R, Geurts van Kessel A . The human T cell transcription factor-1 gene. Structure, localization, and promoter characterization. J Biol Chem. 1992; 267(12):8530-6. View

11.

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

12.

Staffas A, Karlsson C, Persson M, Palmqvist L, Bergo M . Wild-type KRAS inhibits oncogenic KRAS-induced T-ALL in mice. Leukemia. 2014; 29(5):1032-40. DOI: 10.1038/leu.2014.315. View

13.

Rubinfeld B, Robbins P, Albert I, Porfiri E, Polakis P . Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science. 1997; 275(5307):1790-2. DOI: 10.1126/science.275.5307.1790. View

14.

Downward J . Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003; 3(1):11-22. DOI: 10.1038/nrc969. View

15.

Hu Y, Smyth G . ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 2009; 347(1-2):70-8. DOI: 10.1016/j.jim.2009.06.008. View

16.

Degryse S, de Bock C, Cox L, Demeyer S, Gielen O, Mentens N . JAK3 mutants transform hematopoietic cells through JAK1 activation, causing T-cell acute lymphoblastic leukemia in a mouse model. Blood. 2014; 124(20):3092-100. DOI: 10.1182/blood-2014-04-566687. View

17.

de The H, Pandolfi P, Chen Z . Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure. Cancer Cell. 2017; 32(5):552-560. DOI: 10.1016/j.ccell.2017.10.002. View

18.

Rosenbauer F, Owens B, Yu L, Tumang J, Steidl U, Kutok J . Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1. Nat Genet. 2005; 38(1):27-37. DOI: 10.1038/ng1679. View

19.

Uhrig S, Ellermann J, Walther T, Burkhardt P, Frohlich M, Hutter B . Accurate and efficient detection of gene fusions from RNA sequencing data. Genome Res. 2021; 31(3):448-460. PMC: 7919457. DOI: 10.1101/gr.257246.119. View

20.

McLaren W, Gil L, Hunt S, Riat H, Ritchie G, Thormann A . The Ensembl Variant Effect Predictor. Genome Biol. 2016; 17(1):122. PMC: 4893825. DOI: 10.1186/s13059-016-0974-4. View