HOTTIP lncRNA Promotes Hematopoietic Stem Cell Self-Renewal Leading to AML-like Disease in Mice

Huacheng Luo; Ganqian Zhu; Jianfeng Xu; Qian Lai; Bowen Yan; Ying Guo; Tsz Kan Fung; Bernd B Zeisig; Ya Cui; Jie Zha; Christopher Cogle; Fei Wang; Bing Xu; Feng-Chun Yang; Wei Li; Chi Wai Eric So; Yi Qiu; Mingjiang Xu; Suming Huang

doi:10.1016/j.ccell.2019.10.011

HOTTIP lncRNA Promotes Hematopoietic Stem Cell Self-Renewal Leading to AML-like Disease in Mice

Cancer Cell. 2019 Dec 9;36(6):645-659.e8. doi: 10.1016/j.ccell.2019.10.011. Epub 2019 Nov 27.

Authors

Huacheng Luo¹, Ganqian Zhu², Jianfeng Xu³, Qian Lai⁴, Bowen Yan⁵, Ying Guo⁶, Tsz Kan Fung⁷, Bernd B Zeisig⁷, Ya Cui⁸, Jie Zha⁹, Christopher Cogle¹⁰, Fei Wang¹¹, Bing Xu⁹, Feng-Chun Yang¹², Wei Li⁸, Chi Wai Eric So¹³, Yi Qiu¹⁴, Mingjiang Xu¹⁵, Suming Huang¹⁶

Affiliations

¹ Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
² Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136.
³ Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
⁵ Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
⁶ Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136; Department of Cell System & Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
⁷ School of Cancer and Pharmaceutical Science, King's College London, London SE5 9NU, UK.
⁸ Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biological Chemistry, University of California Irvine, Irvine, CA 92697, USA.
⁹ Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
¹⁰ Division of Hematology/Oncology, Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
¹¹ Department of Hematology and Oncology, The Affiliated Zhongda Hospital, Southeast University Medical School, Nanjing 210009, China.
¹² Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136; Department of Cell System & Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
¹³ School of Cancer and Pharmaceutical Science, King's College London, London SE5 9NU, UK. Electronic address: eric.so@kcl.ac.uk.
¹⁴ Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA. Electronic address: qiuy@ufl.edu.
¹⁵ Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136; Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. Electronic address: xum1@uthscsa.edu.
¹⁶ Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. Electronic address: shuang4@pennstatehealth.psu.edu.

Abstract

Long non-coding RNAs (lncRNAs) are critical for regulating HOX genes, aberration of which is a dominant mechanism for leukemic transformation. How HOX gene-associated lncRNAs regulate hematopoietic stem cell (HSC) function and contribute to leukemogenesis remains elusive. We found that HOTTIP is aberrantly activated in acute myeloid leukemia (AML) to alter HOXA-driven topologically associated domain (TAD) and gene expression. HOTTIP loss attenuates leukemogenesis of transplanted mice, while reactivation of HOTTIP restores leukemic TADs, transcription, and leukemogenesis in the CTCF-boundary-attenuated AML cells. Hottip aberration in mice abnormally promotes HSC self-renewal leading to AML-like disease by altering the homeotic/hematopoietic gene-associated chromatin signature and transcription program. Hottip aberration acts as an oncogenic event to perturb HSC function by reprogramming leukemic-associated chromatin and gene transcription.

Keywords: CTCF boundary; HOTTIP lncRNA; HOTTIP transgenic mice; HOX and hematopoietic gene regulation; HSC self-renewal; WNT signaling targets; chromatin domain; enhancer/promoter accessibility; leukemia.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Proliferation / genetics
Cell Self Renewal / genetics*
Chromatin / metabolism
Gene Expression Regulation, Leukemic / genetics*
Gene Knockdown Techniques / methods
Hematopoietic Stem Cells / metabolism
Homeodomain Proteins / genetics
Leukemia, Myeloid, Acute / genetics*
Mice
RNA, Long Noncoding / genetics*

Substances

Chromatin
Homeodomain Proteins
RNA, Long Noncoding
long noncoding RNA HOTTIP, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding