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ResearchIn-Press PreviewGeneticsHematology Open Access | 10.1172/JCI184743

HoxBlinc lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98-rearranged leukemia

Karina Hamamoto,1 Ganqian Zhu,2 Qian Lai,1 Julia Lesperance,1 Huacheng Luo,1 Ying Li,2 Nupur Nigam,3 Arati Sharma,4 Feng-Chun Yang,5 David Claxton,6 Yi Qiu,7 Peter D. Aplan,3 Mingjiang Xu,2 and Suming Huang1

1Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, United States of America

2Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

3Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

4Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, United States of America

5Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

6Division of Hematology/Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, United States of America

7Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, United States of America

Find articles by Hamamoto, K. in: JCI | PubMed | Google Scholar

1Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, United States of America

2Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

3Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

4Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, United States of America

5Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

6Division of Hematology/Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, United States of America

7Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, United States of America

Find articles by Zhu, G. in: JCI | PubMed | Google Scholar

1Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, United States of America

2Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

3Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

4Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, United States of America

5Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

6Division of Hematology/Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, United States of America

7Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, United States of America

Find articles by Lai, Q. in: JCI | PubMed | Google Scholar

1Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, United States of America

2Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

3Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

4Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, United States of America

5Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

6Division of Hematology/Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, United States of America

7Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, United States of America

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

1Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, United States of America

2Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

3Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

4Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, United States of America

5Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

6Division of Hematology/Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, United States of America

7Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, United States of America

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

1Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, United States of America

2Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

3Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

4Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, United States of America

5Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

6Division of Hematology/Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, United States of America

7Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, United States of America

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

1Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, United States of America

2Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

3Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

4Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, United States of America

5Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

6Division of Hematology/Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, United States of America

7Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, United States of America

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

1Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, United States of America

2Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

3Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

4Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, United States of America

5Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

6Division of Hematology/Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, United States of America

7Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, United States of America

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

1Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, United States of America

2Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

3Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

4Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, United States of America

5Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

6Division of Hematology/Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, United States of America

7Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, United States of America

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

1Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, United States of America

2Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

3Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

4Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, United States of America

5Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

6Division of Hematology/Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, United States of America

7Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, United States of America

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

1Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, United States of America

2Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

3Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

4Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, United States of America

5Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

6Division of Hematology/Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, United States of America

7Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, United States of America

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

1Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, United States of America

2Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

3Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

4Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, United States of America

5Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

6Division of Hematology/Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, United States of America

7Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, United States of America

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

1Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, United States of America

2Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

3Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

4Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, United States of America

5Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

6Division of Hematology/Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, United States of America

7Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, United States of America

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

1Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, United States of America

2Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

3Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, United States of America

4Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, United States of America

5Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, United States of America

6Division of Hematology/Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, United States of America

7Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, United States of America

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

Published January 30, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI184743.
Copyright © 2025, Hamamoto 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 January 30, 2025 - Version history
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Abstract

Although nucleoporin 98 (NUP98) fusion oncogenes often drive aggressive pediatric leukemia by altering chromatin structure and expression of HOX genes, underlying mechanisms remain elusive. Here, we report that a Hoxb-associated lncRNA HoxBlinc was aberrantly activated in NUP98-PHF23 fusion-driven leukemias. HoxBlinc chromatin occupancies led to elevated MLL1 recruitment and aberrant homeotic topologically associated domains (TADs) that enhanced chromatin accessibilities and activated homeotic/hematopoietic oncogenes. HoxBlinc-depletion in NUP98 fusion-driven leukemia impaired HoxBlinc binding, TAD integrity, MLL1 recruitment, and MLL1-driven chromatin signature within HoxBlinc-defined TADs in a CTCF-independent manner, leading to inhibited homeotic/leukemic oncogenes that mitigated NUP98 fusion-driven leukemogenesis in xenografted mouse models. Mechanistically, HoxBlinc overexpression in mouse hematopoietic compartment induced leukemias resembling those in NUP98-PHF23 knock-in mice via enhancing HoxBlinc chromatin binding, TAD formation, and Hox gene aberration leading to expansion of hematopoietic stem and progenitor cell (HSPC) and myeloid/lymphoid subpopulations. Thus, our studies reveal a CTCF-independent role of HoxBlinc in leukemic TAD organization and oncogene regulatory networks.

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  • Version 1 (January 30, 2025): In-Press Preview
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