Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia
Van Thillo, Q
De Bie, J
Seneviratne, JA
Demeyer, S
Omari, S
Balachandran, A
Zhai, V
Tam, WL
Sweron, B
Geerdens, E
Gielen, O
Provost, S
Segers, H
Boeckx, N
Marshall, GM
Cheung, BB
Isobe, K
Kato, I
Takita, J
Amos, TG
Deveson, IW
McCalmont, H
Lock, RB
Oxley, EP
Garwood, MM
Dickins, RA
Uyttebroeck, A
Carter, DR
Cools, J
de Bock, CE
- Publisher:
- Nature Research
- Publication Type:
- Journal Article
- Citation:
- Nature Communications, 2021, 12, (1), pp. 1-15
- Issue Date:
- 2021-07-06
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Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Van Thillo, Q | |
dc.contributor.author | De Bie, J | |
dc.contributor.author | Seneviratne, JA | |
dc.contributor.author | Demeyer, S | |
dc.contributor.author | Omari, S | |
dc.contributor.author | Balachandran, A | |
dc.contributor.author | Zhai, V | |
dc.contributor.author | Tam, WL | |
dc.contributor.author | Sweron, B | |
dc.contributor.author | Geerdens, E | |
dc.contributor.author | Gielen, O | |
dc.contributor.author | Provost, S | |
dc.contributor.author | Segers, H | |
dc.contributor.author | Boeckx, N | |
dc.contributor.author | Marshall, GM | |
dc.contributor.author | Cheung, BB | |
dc.contributor.author | Isobe, K | |
dc.contributor.author | Kato, I | |
dc.contributor.author | Takita, J | |
dc.contributor.author | Amos, TG | |
dc.contributor.author | Deveson, IW | |
dc.contributor.author | McCalmont, H | |
dc.contributor.author | Lock, RB | |
dc.contributor.author | Oxley, EP | |
dc.contributor.author | Garwood, MM | |
dc.contributor.author | Dickins, RA | |
dc.contributor.author | Uyttebroeck, A | |
dc.contributor.author | Carter, DR | |
dc.contributor.author | Cools, J | |
dc.contributor.author | de Bock, CE | |
dc.date.accessioned | 2022-05-12T07:00:07Z | |
dc.date.available | 2021-06-18 | |
dc.date.available | 2022-05-12T07:00:07Z | |
dc.date.issued | 2021-07-06 | |
dc.identifier.citation | Nature Communications, 2021, 12, (1), pp. 1-15 | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | http://hdl.handle.net/10453/157298 | |
dc.description.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. | |
dc.format | Electronic | |
dc.language | eng | |
dc.publisher | Nature Research | |
dc.relation.ispartof | Nature Communications | |
dc.relation.isbasedon | 10.1038/s41467-021-24442-9 | |
dc.rights | info:eu-repo/semantics/openAccess | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Bone Marrow Transplantation | |
dc.subject.mesh | Carcinogenesis | |
dc.subject.mesh | Disease Models, Animal | |
dc.subject.mesh | Female | |
dc.subject.mesh | GTP Phosphohydrolases | |
dc.subject.mesh | HEK293 Cells | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Membrane Proteins | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Mice, Inbred C57BL | |
dc.subject.mesh | Mutation | |
dc.subject.mesh | Oncogene Proteins, Fusion | |
dc.subject.mesh | Oncogenes | |
dc.subject.mesh | Precursor T-Cell Lymphoblastic Leukemia-Lymphoma | |
dc.subject.mesh | Proto-Oncogene Mas | |
dc.subject.mesh | Proto-Oncogene Proteins | |
dc.subject.mesh | T Cell Transcription Factor 1 | |
dc.subject.mesh | T-Lymphocytes | |
dc.subject.mesh | Trans-Activators | |
dc.subject.mesh | Transcriptome | |
dc.subject.mesh | beta Catenin | |
dc.subject.mesh | T-Lymphocytes | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Mice, Inbred C57BL | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Disease Models, Animal | |
dc.subject.mesh | GTP Phosphohydrolases | |
dc.subject.mesh | Trans-Activators | |
dc.subject.mesh | Membrane Proteins | |
dc.subject.mesh | Oncogene Proteins, Fusion | |
dc.subject.mesh | Proto-Oncogene Proteins | |
dc.subject.mesh | Bone Marrow Transplantation | |
dc.subject.mesh | Mutation | |
dc.subject.mesh | Oncogenes | |
dc.subject.mesh | Female | |
dc.subject.mesh | beta Catenin | |
dc.subject.mesh | T Cell Transcription Factor 1 | |
dc.subject.mesh | Precursor T-Cell Lymphoblastic Leukemia-Lymphoma | |
dc.subject.mesh | HEK293 Cells | |
dc.subject.mesh | Transcriptome | |
dc.subject.mesh | Carcinogenesis | |
dc.subject.mesh | Proto-Oncogene Mas | |
dc.title | Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia | |
dc.type | Journal Article | |
utslib.citation.volume | 12 | |
utslib.location.activity | England | |
pubs.organisational-group | /University of Technology Sydney | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Engineering and Information Technology | |
pubs.organisational-group | /University of Technology Sydney/Strength - CHT - Health Technologies | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering | |
pubs.organisational-group | /University of Technology Sydney/Centre for Health Technologies (CHT) | |
utslib.copyright.status | open_access | * |
pubs.consider-herdc | false | |
dc.date.updated | 2022-05-12T07:00:00Z | |
pubs.issue | 1 | |
pubs.publication-status | Published | |
pubs.volume | 12 | |
utslib.citation.issue | 1 |
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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