Filip Matthijssens, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
Nitesh D. Sharma, 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
Monique Nysus, 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
Christian K. Nickl, 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
Huining Kang, 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
Dominique R. Perez, Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA.; University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, USA
Beatrice Lintermans, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
Wouter Van Loocke, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
Juliette Roels, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
Sofie Peirs, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
Lisa Demoen, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
Tim Pieters, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
Lindy Reunes, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
Tim Lammens, Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
Barbara De Moerloose, Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
Filip Van Nieuwerburgh, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium
Dieter L. Deforce, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium
Laurence C. Cheung, 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
Rishi S. Kotecha, 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
Martijn Dp Risseeuw, Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium
Serge Van Calenbergh, Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium
Takeshi Takarada, Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Yukio Yoneda, Department of Pharmacology, Osaka University Graduate School of Dentistry, Suita, Japan
Frederik W. van Delft, Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom
Richard B. Lock, 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
Seth D. Merkley, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
Alexandre Chigaev, Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA.; University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, USA
Larry A. Sklar, Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA.; University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, USA
Charles G. Mullighan, Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Mignon L. Loh, Department of Pediatrics, Benioff Children's Hospital, UCSF, San Francisco, California, USA
Stuart S. Winter, Cancer and Blood Disorders Program, Children's Minnesota, Minneapolis, Minnesota, USA
Stephen P. Hunger, 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
Steven Goossens, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
Eliseo F. Castillo, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
Wojciech Ornatowski, Department of Medicine, University of Arizona, Tucson, Arizona, USA
Pieter Van Vlierberghe, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
Ksenia Matlawska-Wasowska, 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

Document Type

Article

Publication Date

3-15-2021

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 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.

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