RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia.

Autor: Matthijssens F; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Sharma ND; Department of Pediatrics, Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.; Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA., Nysus M; Department of Pediatrics, Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.; Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA., Nickl CK; Department of Pediatrics, Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.; Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA., Kang H; Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA.; Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA., Perez DR; Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA.; University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, USA., Lintermans B; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Van Loocke W; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Roels J; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Peirs S; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Demoen L; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Pieters T; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Reunes L; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Lammens T; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.; Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium., De Moerloose B; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.; Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium., Van Nieuwerburgh F; Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium., Deforce DL; Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium., Cheung LC; Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.; School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Western Australia, Australia., Kotecha RS; Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.; School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Western Australia, Australia., Risseeuw MD; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.; Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium., Van Calenbergh S; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.; Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium., Takarada T; Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan., Yoneda Y; Department of Pharmacology, Osaka University Graduate School of Dentistry, Suita, Japan., van Delft FW; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom., Lock RB; Children's Cancer Institute, School of Women's and Children's Health, Lowy Cancer Centre, University of New South Wales, Sydney, New South Wales, Australia., Merkley SD; Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA., Chigaev A; Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA.; University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, USA., Sklar LA; Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA.; University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, USA., Mullighan CG; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Loh ML; Department of Pediatrics, Benioff Children's Hospital, UCSF, San Francisco, California, USA., Winter SS; Cancer and Blood Disorders Program, Children's Minnesota, Minneapolis, Minnesota, USA., Hunger SP; Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Goossens S; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.; Department of Diagnostic Sciences, Ghent University, Ghent, Belgium., Castillo EF; Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA., Ornatowski W; Department of Medicine, University of Arizona, Tucson, Arizona, USA., Van Vlierberghe P; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Matlawska-Wasowska K; Department of Pediatrics, Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.; Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2021 Mar 15; Vol. 131 (6).
DOI: 10.1172/JCI141566
Abstrakt: 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 CBFβ. 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.
Databáze: MEDLINE