Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia

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

doi:10.1038/s41467-021-24442-9

Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia

Nat Commun. 2021 Jul 6;12(1):4164. doi: 10.1038/s41467-021-24442-9.

Authors

Quentin Van Thillo^#^{1

2

3}, Jolien De Bie^#^{1

2

4}, Janith A Seneviratne^{5

6}, Sofie Demeyer^{1

2

3}, Sofia Omari^{5

6}, Anushree Balachandran^{5

6}, Vicki Zhai^{5

6}, Wai L Tam⁷, Bram Sweron^{1

2}, Ellen Geerdens^{1

2

3}, Olga Gielen^{1

2}, Sarah Provost^{1

2}, Heidi Segers^{3

8

9}, Nancy Boeckx^{8

10}, Glenn M Marshall^{5

6

11}, Belamy B Cheung^{5

6}, Kiyotaka Isobe¹², Itaru Kato¹², Junko Takita¹², Timothy G Amos¹³, Ira W Deveson^{13

14}, Hannah McCalmont^{5

6}, Richard B Lock^{5

6}, Ethan P Oxley¹⁵, Maximilian M Garwood¹⁵, Ross A Dickins¹⁵, Anne Uyttebroeck^{3

8

9}, Daniel R Carter^{5

6

16}, Jan Cools^{17

18

19}, Charles E de Bock^{20

21}

Affiliations

¹ Department of Human Genetics, KU Leuven, Leuven, Belgium.
² Center for Cancer Biology, VIB, Leuven, Belgium.
³ Leuvens Kanker Instituut (LKI), KU Leuven - UZ Leuven, Leuven, Belgium.
⁴ Center for Human Genetics, UZ Leuven, Leuven, Belgium.
⁵ Children's Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre, Sydney, NSW, Australia.
⁶ School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia.
⁷ Technology Innovation Lab, VIB, Gent, Belgium.
⁸ Department of Oncology, KU Leuven, Leuven, Belgium.
⁹ Department of Pediatric Hemato-Oncology, UZ Leuven, Leuven, Belgium.
¹⁰ Department of Laboratory Medicine, UZ Leuven, Leuven, Belgium.
¹¹ Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia.
¹² Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹³ Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.
¹⁴ St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia.
¹⁵ Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
¹⁶ School of Biomedical Engineering, University of Technology, Sydney, NSW, Australia.
¹⁷ Department of Human Genetics, KU Leuven, Leuven, Belgium. [email protected].
¹⁸ Center for Cancer Biology, VIB, Leuven, Belgium. [email protected].
¹⁹ Leuvens Kanker Instituut (LKI), KU Leuven - UZ Leuven, Leuven, Belgium. [email protected].
²⁰ Children's Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre, Sydney, NSW, Australia. [email protected].
²¹ School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Marrow Transplantation
Carcinogenesis / genetics
Disease Models, Animal
Female
GTP Phosphohydrolases / genetics
GTP Phosphohydrolases / metabolism*
HEK293 Cells
Humans
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Inbred C57BL
Mutation
Oncogene Proteins, Fusion / genetics
Oncogene Proteins, Fusion / metabolism
Oncogenes
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
Proto-Oncogene Mas
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*
T Cell Transcription Factor 1 / genetics
T Cell Transcription Factor 1 / metabolism*
T-Lymphocytes / metabolism
Trans-Activators / genetics
Trans-Activators / metabolism*
Transcriptome
beta Catenin / genetics
beta Catenin / metabolism*

Substances

MAS1 protein, human
Membrane Proteins
Oncogene Proteins, Fusion
Proto-Oncogene Mas
Proto-Oncogene Proteins
T Cell Transcription Factor 1
TCF7 protein, human
Trans-Activators
beta Catenin
proto-oncogene protein Spi-1
GTP Phosphohydrolases
NRAS protein, human