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ResearchIn-Press PreviewOncology Free access | 10.1172/JCI141566

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

Filip Matthijssens,1 Nitesh D. Sharma,2 Monique Nysus,2 Christian K. Nickl,2 Huining Kang,2 Dominique R. Perez,3 Beatrice Lintermans,1 Wouter Van Loocke,1 Juliette Roels,1 Sofie Peirs,1 Lisa Demoen,1 Tim Pieters,1 Lindy Reunes,1 Tim Lammens,4 Barbara De Moerloose,4 Filip Van Nieuwerburgh,5 Dieter L. Deforce,5 Laurence C. Cheung,6 Rishi S. Kotecha,6 Martijn D. P. Risseeuw,7 Serge Van Calenbergh,7 Takeshi Takarada,8 Yukio Yoneda,9 Frederik W. van Delft,10 Richard B. Lock,11 Seth D. Merkley,12 Alexandre Chigaev,13 Larry A. Sklar,13 Charles G. Mullighan,14 Mignon L. Loh,15 Stuart S. Winter,16 Stephen P. Hunger,17 Steven Goossens,1 Eliseo F. Castillo,12 Wojciech Ornatowski,18 Pieter Van Vlierberghe,1 and Ksenia Matlawska-Wasowska19

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Matthijssens, F. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Sharma, N. in: JCI | PubMed | Google Scholar

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Nysus, M. in: JCI | PubMed | Google Scholar

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Nickl, C. in: JCI | PubMed | Google Scholar

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Kang, H. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Perez, D. in: JCI | PubMed | Google Scholar

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Lintermans, B. in: JCI | PubMed | Google Scholar

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Van Loocke, W. in: JCI | PubMed | Google Scholar

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Roels, J. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Peirs, S. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Demoen, L. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Pieters, T. in: JCI | PubMed | Google Scholar

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Reunes, L. in: JCI | PubMed | Google Scholar

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Lammens, T. in: JCI | PubMed | Google Scholar

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by De Moerloose, B. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Van Nieuwerburgh, F. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Deforce, D. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Cheung, L. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Kotecha, R. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Risseeuw, M. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Van Calenbergh, S. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Takarada, T. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Yoneda, Y. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by van Delft, F. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Lock, R. in: JCI | PubMed | Google Scholar

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Merkley, S. in: JCI | PubMed | Google Scholar

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Chigaev, A. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Sklar, L. in: JCI | PubMed | Google Scholar

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Mullighan, C. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Loh, M. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Winter, S. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Hunger, S. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Goossens, S. in: JCI | PubMed | Google Scholar

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Castillo, E. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Ornatowski, W. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Van Vlierberghe, P. in: JCI | PubMed | Google Scholar |

1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

2Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, United States of America

3Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, United States of America

4Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

5Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

6Telethon Kids Cancer Centre, University of Western Australia, Perth, Australia

7Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium

8Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan

9Department of Pharmacology, Osaka University Graduate School of Dentistry, Kanazawa, Japan

10Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle, United Kingdom

11Children's Cancer Institute, University of New South Wales, Sydney, Australia

12Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States of America

13Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States of America

14Department of Pathology, St. Jude Children`s Research Hospital, Memphis, United States of America

15Department of Pediatrics, UCSF, San Francisco, United States of America

16Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, United States of America

17Department of Pediatrics and the Center for Childhood Cancer Research, University of Pennsylvania, Philadelphia, United States of America

18Department of Medicine, University of Arizona, Arizona, United States of America

19Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, United States of America

Find articles by Matlawska-Wasowska, K. in: JCI | PubMed | Google Scholar |

Published February 8, 2021 - More info

J Clin Invest. https://doi.org/10.1172/JCI141566.
Copyright © 2021, American Society for Clinical Investigation
Published February 8, 2021 - Version history
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Abstract

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.

Graphical Abstract
graphical abstract
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