RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared to B-cell ALL. Here, we showed that Runt-related transcription factor 2, RUNX2 was upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or an immature immunophenotype. In...
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| Format: | Journal Article |
| Language: | English |
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2021
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| Online Access: | http://purl.org/au-research/grants/nhmrc/1142627 http://hdl.handle.net/20.500.11937/82712 |
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| author | Matthijssens, Filip Sharma, Nitesh D Nysus, Monique Nickl, Christian K Kang, Huining Perez, Dominique R Lintermans, Beatrice Van Loocke, Wouter Roels, Juliette Peirs, Sofie Demoen, Lisa Pieters, Tim Reunes, Lindy Lammens, Tim De Moerloose, Barbara Van Nieuwerburgh, Filip Deforce, Dieter L Cheung, Laurence Kotecha, Rishi Risseeuw, Martijn DP Van Calenbergh, Serge Takarada, Takeshi Yoneda, Yukio van Delft, Frederik W Lock, Richard B Merkley, Seth D Chigaev, Alexandre Sklar, Larry A Mullighan, Charles G Loh, Mignon L Winter, Stuart S Hunger, Stephen P Goossens, Steven Castillo, Eliseo F Ornatowski, Wojciech Van Vlierberghe, Pieter Matlawska-Wasowska, Ksenia |
| author_facet | Matthijssens, Filip Sharma, Nitesh D Nysus, Monique Nickl, Christian K Kang, Huining Perez, Dominique R Lintermans, Beatrice Van Loocke, Wouter Roels, Juliette Peirs, Sofie Demoen, Lisa Pieters, Tim Reunes, Lindy Lammens, Tim De Moerloose, Barbara Van Nieuwerburgh, Filip Deforce, Dieter L Cheung, Laurence Kotecha, Rishi Risseeuw, Martijn DP Van Calenbergh, Serge Takarada, Takeshi Yoneda, Yukio van Delft, Frederik W Lock, Richard B Merkley, Seth D Chigaev, Alexandre Sklar, Larry A Mullighan, Charles G Loh, Mignon L Winter, Stuart S Hunger, Stephen P Goossens, Steven Castillo, Eliseo F Ornatowski, Wojciech Van Vlierberghe, Pieter Matlawska-Wasowska, Ksenia |
| author_sort | Matthijssens, Filip |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared to B-cell ALL. Here, we showed that Runt-related transcription factor 2, RUNX2 was upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or an immature immunophenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, where it reciprocally bound the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 was required for survival of immature and KMT2A-R T-ALL cells in vitro and in vivo. We reported direct transcriptional regulation of CXCR4 signaling by RUNX2, thereby promoting chemotaxis, adhesion and homing to medullary and extramedullary sites. RUNX2 enabled these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation increased mitochondrial dynamics and biogenesis in T-ALL cells. Finally, as a proof of concept, we demonstrated that immature and KMT2A-R T-ALL cells were vulnerable to pharmacological targeting of the interaction between RUNX2 and its co-factor CBFβ. In conclusion, we showed that RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL through concomitant regulation of tumour metabolism and leukemic cell migration. |
| first_indexed | 2025-11-14T11:20:56Z |
| format | Journal Article |
| id | curtin-20.500.11937-82712 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | eng |
| last_indexed | 2025-11-14T11:20:56Z |
| publishDate | 2021 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-827122021-03-18T03:53:24Z RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia. Matthijssens, Filip Sharma, Nitesh D Nysus, Monique Nickl, Christian K Kang, Huining Perez, Dominique R Lintermans, Beatrice Van Loocke, Wouter Roels, Juliette Peirs, Sofie Demoen, Lisa Pieters, Tim Reunes, Lindy Lammens, Tim De Moerloose, Barbara Van Nieuwerburgh, Filip Deforce, Dieter L Cheung, Laurence Kotecha, Rishi Risseeuw, Martijn DP Van Calenbergh, Serge Takarada, Takeshi Yoneda, Yukio van Delft, Frederik W Lock, Richard B Merkley, Seth D Chigaev, Alexandre Sklar, Larry A Mullighan, Charles G Loh, Mignon L Winter, Stuart S Hunger, Stephen P Goossens, Steven Castillo, Eliseo F Ornatowski, Wojciech Van Vlierberghe, Pieter Matlawska-Wasowska, Ksenia Cell migration/adhesion Leukemias Molecular biology Oncology T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared to B-cell ALL. Here, we showed that Runt-related transcription factor 2, RUNX2 was upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or an immature immunophenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, where it reciprocally bound the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 was required for survival of immature and KMT2A-R T-ALL cells in vitro and in vivo. We reported direct transcriptional regulation of CXCR4 signaling by RUNX2, thereby promoting chemotaxis, adhesion and homing to medullary and extramedullary sites. RUNX2 enabled these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation increased mitochondrial dynamics and biogenesis in T-ALL cells. Finally, as a proof of concept, we demonstrated that immature and KMT2A-R T-ALL cells were vulnerable to pharmacological targeting of the interaction between RUNX2 and its co-factor CBFβ. In conclusion, we showed that RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL through concomitant regulation of tumour metabolism and leukemic cell migration. 2021 Journal Article http://hdl.handle.net/20.500.11937/82712 10.1172/JCI141566 eng http://purl.org/au-research/grants/nhmrc/1142627 http://purl.org/au-research/grants/nhmrc/1059804 http://purl.org/au-research/grants/nhmrc/1157871 fulltext |
| spellingShingle | Cell migration/adhesion Leukemias Molecular biology Oncology Matthijssens, Filip Sharma, Nitesh D Nysus, Monique Nickl, Christian K Kang, Huining Perez, Dominique R Lintermans, Beatrice Van Loocke, Wouter Roels, Juliette Peirs, Sofie Demoen, Lisa Pieters, Tim Reunes, Lindy Lammens, Tim De Moerloose, Barbara Van Nieuwerburgh, Filip Deforce, Dieter L Cheung, Laurence Kotecha, Rishi Risseeuw, Martijn DP Van Calenbergh, Serge Takarada, Takeshi Yoneda, Yukio van Delft, Frederik W Lock, Richard B Merkley, Seth D Chigaev, Alexandre Sklar, Larry A Mullighan, Charles G Loh, Mignon L Winter, Stuart S Hunger, Stephen P Goossens, Steven Castillo, Eliseo F Ornatowski, Wojciech Van Vlierberghe, Pieter Matlawska-Wasowska, Ksenia RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia. |
| title | RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia. |
| title_full | RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia. |
| title_fullStr | RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia. |
| title_full_unstemmed | RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia. |
| title_short | RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia. |
| title_sort | runx2 regulates leukemic cell metabolism and chemotaxis in high-risk t cell acute lymphoblastic leukemia. |
| topic | Cell migration/adhesion Leukemias Molecular biology Oncology |
| url | http://purl.org/au-research/grants/nhmrc/1142627 http://purl.org/au-research/grants/nhmrc/1142627 http://purl.org/au-research/grants/nhmrc/1142627 http://hdl.handle.net/20.500.11937/82712 |