RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia
- Author
- Filip Matthijssens (UGent) , Nitesh D. Sharma, Monique Nysus, Christian K. Nickl, Huining Kang, Dominique R. Perez, Béatrice Lintermans (UGent) , Wouter Van Loocke (UGent) , Juliette Roels (UGent) , Sofie Peirs (UGent) , Lisa Demoen (UGent) , Tim Pieters (UGent) , Lindy Reunes (UGent) , Tim Lammens (UGent) , Barbara De Moerloose (UGent) , Filip Van Nieuwerburgh (UGent) , Dieter Deforce (UGent) , Laurence C. Cheung, Rishi S. Kotecha, Martijn Risseeuw (UGent) , Serge Van Calenbergh (UGent) , Takeshi Takarada, Yukio Yoneda, Frederik W. van Delft, Richard B. Lock, Seth D. Merkley, Alexandre Chigaev, Larry A. Sklar, Charles G. Mullighan, Mignon L. Loh, Stuart S. Winter, Stephen P. Hunger, Steven Goossens (UGent) , Eliseo F. Castillo, Wojciech Ornatowski, Pieter Van Vlierberghe (UGent) and Ksenia Matlawska-Wasowska
- Organization
- Abstract
- T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared with that of B cell ALL. Here, we show 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 report 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 demonstrate that immature and KMT2A-R T-ALL cells were vulnerable to pharmacological targeting of the interaction between RUNX2 and its cofactor CBF beta. In conclusion, we show that RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL through concomitant regulation of tumor metabolism and leukemic cell migration.
- Keywords
- GENE-EXPRESSION SIGNATURES, CHEMOKINE RECEPTOR CXCR4, ACUTE MYELOID-LEUKEMIA, BETA-CATENIN, STEM-CELLS, OSTEOBLAST DIFFERENTIATION, TARGETING SURVIVIN, DRUG-RESISTANCE, TRANSCRIPTION, LINEAGE
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-8698107
- MLA
- Matthijssens, Filip, et al. “RUNX2 Regulates Leukemic Cell Metabolism and Chemotaxis in High-Risk T Cell Acute Lymphoblastic Leukemia.” JOURNAL OF CLINICAL INVESTIGATION, vol. 131, no. 6, 2021, doi:10.1172/jci141566.
- APA
- Matthijssens, F., Sharma, N. D., Nysus, M., Nickl, C. K., Kang, H., Perez, D. R., … Matlawska-Wasowska, K. (2021). RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia. JOURNAL OF CLINICAL INVESTIGATION, 131(6). https://doi.org/10.1172/jci141566
- Chicago author-date
- Matthijssens, Filip, Nitesh D. Sharma, Monique Nysus, Christian K. Nickl, Huining Kang, Dominique R. Perez, Béatrice Lintermans, et al. 2021. “RUNX2 Regulates Leukemic Cell Metabolism and Chemotaxis in High-Risk T Cell Acute Lymphoblastic Leukemia.” JOURNAL OF CLINICAL INVESTIGATION 131 (6). https://doi.org/10.1172/jci141566.
- Chicago author-date (all authors)
- Matthijssens, Filip, Nitesh D. Sharma, Monique Nysus, Christian K. Nickl, Huining Kang, Dominique R. Perez, Béatrice Lintermans, Wouter Van Loocke, Juliette Roels, Sofie Peirs, Lisa Demoen, Tim Pieters, Lindy Reunes, Tim Lammens, Barbara De Moerloose, Filip Van Nieuwerburgh, Dieter Deforce, Laurence C. Cheung, Rishi S. Kotecha, Martijn Risseeuw, Serge Van Calenbergh, Takeshi Takarada, Yukio Yoneda, Frederik W. van Delft, Richard B. Lock, Seth D. Merkley, Alexandre Chigaev, Larry A. Sklar, Charles G. Mullighan, Mignon L. Loh, Stuart S. Winter, Stephen P. Hunger, Steven Goossens, Eliseo F. Castillo, Wojciech Ornatowski, Pieter Van Vlierberghe, and Ksenia Matlawska-Wasowska. 2021. “RUNX2 Regulates Leukemic Cell Metabolism and Chemotaxis in High-Risk T Cell Acute Lymphoblastic Leukemia.” JOURNAL OF CLINICAL INVESTIGATION 131 (6). doi:10.1172/jci141566.
- Vancouver
- 1.Matthijssens F, Sharma ND, Nysus M, Nickl CK, Kang H, Perez DR, et al. RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia. JOURNAL OF CLINICAL INVESTIGATION. 2021;131(6).
- IEEE
- [1]F. Matthijssens et al., “RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia,” JOURNAL OF CLINICAL INVESTIGATION, vol. 131, no. 6, 2021.
@article{8698107,
abstract = {{T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared with that of B cell ALL. Here, we show 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 report 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 demonstrate that immature and KMT2A-R T-ALL cells were vulnerable to pharmacological targeting of the interaction between RUNX2 and its cofactor CBF beta. In conclusion, we show that RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL through concomitant regulation of tumor metabolism and leukemic cell migration.}},
articleno = {{e141566}},
author = {{Matthijssens, Filip and Sharma, Nitesh D. and Nysus, Monique and Nickl, Christian K. and Kang, Huining and Perez, Dominique R. and Lintermans, Béatrice and Van Loocke, Wouter and Roels, Juliette and Peirs, Sofie and Demoen, Lisa and Pieters, Tim and Reunes, Lindy and Lammens, Tim and De Moerloose, Barbara and Van Nieuwerburgh, Filip and Deforce, Dieter and Cheung, Laurence C. and Kotecha, Rishi S. and Risseeuw, Martijn and Van Calenbergh, Serge and Takarada, Takeshi and Yoneda, Yukio and van Delft, Frederik W. and Lock, Richard B. and Merkley, Seth D. and Chigaev, Alexandre and Sklar, Larry A. and Mullighan, Charles G. and Loh, Mignon L. and Winter, Stuart S. and Hunger, Stephen P. and Goossens, Steven and Castillo, Eliseo F. and Ornatowski, Wojciech and Van Vlierberghe, Pieter and Matlawska-Wasowska, Ksenia}},
issn = {{0021-9738}},
journal = {{JOURNAL OF CLINICAL INVESTIGATION}},
keywords = {{GENE-EXPRESSION SIGNATURES,CHEMOKINE RECEPTOR CXCR4,ACUTE MYELOID-LEUKEMIA,BETA-CATENIN,STEM-CELLS,OSTEOBLAST DIFFERENTIATION,TARGETING SURVIVIN,DRUG-RESISTANCE,TRANSCRIPTION,LINEAGE}},
language = {{eng}},
number = {{6}},
pages = {{20}},
title = {{RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia}},
url = {{http://doi.org/10.1172/jci141566}},
volume = {{131}},
year = {{2021}},
}
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