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ResearchIn-Press PreviewCell biologyHematologyOncology Open Access | 10.1172/JCI187998

The hematopoietic stem cell MYB enhancer is essential and recurrently amplified during T-cell leukemogenesis

Carea Mullin,1 Karena Lin,2 Elizabeth Choe,1 Cher Sha,3 Zeel Shukla,1 Koral Campbell,4 Anna C. McCarter,5 Annie Wang,1 Jannaldo Nieves-Salva,6 Sarah Khan,1 Theresa M. Keeley,7 Shannon Liang,1 Qing Wang,1 Ashley F. Melnick,2 Pearl Evans,1 Alexander C. Monovich,3 Ashwin Iyer,8 Rohan Kodgule,9 Yamei Deng,10 Felipe da Veiga Leprevost,10 Kelly R. Barnett,11 Petri Pölönen,12 Rami Khoriaty,1 Daniel Savic,11 David T. Teachey,13 Charles G. Mullighan,12 Marcin Cieslik,14 Alexey I. Nesvizhskii,14 Linda C. Samuelson,15 Morgan Jones,16 Qing Li,16 Russell J.H. Ryan,17 and Mark Y. Chiang16

1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, United States of America

2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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2Cellular and Molecular Biology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

3Immunology and Microbiology Program, Baylor College of Medicine, Houston, United States of America

4Molecular and Cellular Pathology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

5Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, United States of America

6Immunology Program, University of Michigan School of Medicine, Ann Arbor, United States of America

7Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United States of America

8Regeneron Pharmaceuticals, Tarrytown, United States of America

9Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

10Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

11Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, United States of America

12Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States of America

13Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America

14Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States of America

15Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

16Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

17Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

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Published October 23, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI187998.
Copyright © 2025, Mullin et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 23, 2025 - Version history
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Abstract

There is an urgent need to find targeted agents for T-cell acute lymphoblastic leukemia (T-ALL). NOTCH1 is the most frequently mutated oncogene in T-ALL, but clinical trials showed that pan-Notch inhibitors caused dose-limiting toxicities. Thus, we shifted our focus to ETS1, which is one of the transcription factors that most frequently co-bind Notch-occupied regulatory elements in the T-ALL context. To identify the most essential enhancers, we performed a genome-wide CRISPR interference screen of the strongest ETS1-dependent regulatory elements. The #1-ranked element is located in an intron of AHI1 that interacts with the MYB promoter and is amplified with MYB in ~8.5% of T-ALL patients. Using mouse models, we showed that this enhancer promotes self-renewal of hematopoietic stem cells and T-cell leukemogenesis, maintains early T-cell precursors, and restrains myeloid expansion with aging. We named this enhancer the hematopoietic stem cell MYB enhancer (H-Me). The H-Me shows limited activity and function in committed T-cell progenitors but is accessed during leukemogenesis. In one T-ALL context, ETS1 binds the ETS motif in the H-Me to recruit cBAF to promote chromatin accessibility and activation. ETS1 or cBAF degraders impaired H-Me function. Thus, we identified a targetable stem cell element that is co-opted for T-cell transformation.

Graphical Abstract
graphical abstract
Supplemental material

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  • Version 1 (October 23, 2025): In-Press Preview
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