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

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

^*Corresponding author for this work

Comprehensive Cancer Centre

The First Affiliated Hospital of Xiamen University
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
Baylor College of Medicine
University of Florida
Department of Cell System & Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
University of California, Irvine
Department of Hematology and Oncology, The Affiliated Zhongda Hospital, Southeast University Medical School, Nanjing 210009, China
Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
University of Texas Health Science Center at San Antonio

Research output: Contribution to journal › Article › peer-review

122 Citations (Scopus)

216 Downloads (Pure)

Abstract

Long non-coding RNAs (lncRNAs) play a critical role in regulating HOX genes of which aberration becomes a dominant mechanism for leukemic transformation. How HOX-associated lncRNAs regulate HSC function and contribute to leukemogenesis remains elusive. We found that HOTTIP is aberrantly activated in AML patients to alter the HOXA-driven topologically associated domain (TAD) and gene expression. HOTTIP loss attenuates leukemogenesis of transplanted AML mice, while reactivation of HOTTIP restores leukemic TADs, chromatin signature, 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 homeotic/hematopoietic gene-associated chromatin signature and transcription program. Thus, Hottip aberration acts as an oncogenic event to perturb HSC function by reprograming leukemic-associated chromatin and gene transcription.

Original language	English
Pages (from-to)	645-659.E8
Journal	CANCER CELL
Volume	36
Issue number	6
Early online date	27 Nov 2019
DOIs	https://doi.org/10.1016/j.ccell.2019.10.011
Publication status	Published - 9 Dec 2019

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccell.2019.10.011

HOTTIP lncRNA promotes_LUO__Acc24Oct2019Epub27Nov2019_GREEN AAMAccepted author manuscript, 4.71 MBLicence: CC BY-NC-ND

Cite this

Luo, H., Zhu, G., Xu, J., Lai, Q., Yan, B., Guo, Y., Fung, T. K., Zeisig, B. B., Cui, Y., Zha, J., Cogle, C., Wang, F., Xu, B., Yang, F. C., Li, W., So, C. W. E., Qiu, Y., Xu, M., & Huang, S. (2019). HOTTIP lncRNA Promotes Hematopoietic Stem Cell Self-Renewal Leading to AML-like Disease in Mice. CANCER CELL, 36(6), 645-659.E8. https://doi.org/10.1016/j.ccell.2019.10.011

@article{70ccd37165ad48dd9dd4e10978ed39c1,

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

abstract = "Long non-coding RNAs (lncRNAs) play a critical role in regulating HOX genes of which aberration becomes a dominant mechanism for leukemic transformation. How HOX-associated lncRNAs regulate HSC function and contribute to leukemogenesis remains elusive. We found that HOTTIP is aberrantly activated in AML patients to alter the HOXA-driven topologically associated domain (TAD) and gene expression. HOTTIP loss attenuates leukemogenesis of transplanted AML mice, while reactivation of HOTTIP restores leukemic TADs, chromatin signature, 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 homeotic/hematopoietic gene-associated chromatin signature and transcription program. Thus, Hottip aberration acts as an oncogenic event to perturb HSC function by reprograming leukemic-associated chromatin and gene transcription.",

keywords = "chromatin domain, CTCF boundary, enhancer/promoter accessibility, HOTTIP lncRNA, HOTTIP transgenic mice, HOX and hematopoietic gene regulation, HSC self-renewal, leukemia, WNT signaling targets",

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

year = "2019",

month = dec,

day = "9",

doi = "10.1016/j.ccell.2019.10.011",

language = "English",

volume = "36",

pages = "645--659.E8",

journal = "CANCER CELL",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - HOTTIP lncRNA Promotes Hematopoietic Stem Cell Self-Renewal Leading to AML-like Disease in Mice

AU - Luo, Huacheng

AU - Zhu, Ganqian

AU - Xu, Jianfeng

AU - Lai, Qian

AU - Yan, Bowen

AU - Guo, Ying

AU - Fung, Tsz Kan

AU - Zeisig, Bernd B.

AU - Cui, Ya

AU - Zha, Jie

AU - Cogle, Christopher

AU - Wang, Fei

AU - Xu, Bing

AU - Yang, Feng Chun

AU - Li, Wei

AU - So, Chi Wai Eric

AU - Qiu, Yi

AU - Xu, Mingjiang

AU - Huang, Suming

PY - 2019/12/9

Y1 - 2019/12/9

N2 - Long non-coding RNAs (lncRNAs) play a critical role in regulating HOX genes of which aberration becomes a dominant mechanism for leukemic transformation. How HOX-associated lncRNAs regulate HSC function and contribute to leukemogenesis remains elusive. We found that HOTTIP is aberrantly activated in AML patients to alter the HOXA-driven topologically associated domain (TAD) and gene expression. HOTTIP loss attenuates leukemogenesis of transplanted AML mice, while reactivation of HOTTIP restores leukemic TADs, chromatin signature, 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 homeotic/hematopoietic gene-associated chromatin signature and transcription program. Thus, Hottip aberration acts as an oncogenic event to perturb HSC function by reprograming leukemic-associated chromatin and gene transcription.

AB - Long non-coding RNAs (lncRNAs) play a critical role in regulating HOX genes of which aberration becomes a dominant mechanism for leukemic transformation. How HOX-associated lncRNAs regulate HSC function and contribute to leukemogenesis remains elusive. We found that HOTTIP is aberrantly activated in AML patients to alter the HOXA-driven topologically associated domain (TAD) and gene expression. HOTTIP loss attenuates leukemogenesis of transplanted AML mice, while reactivation of HOTTIP restores leukemic TADs, chromatin signature, 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 homeotic/hematopoietic gene-associated chromatin signature and transcription program. Thus, Hottip aberration acts as an oncogenic event to perturb HSC function by reprograming leukemic-associated chromatin and gene transcription.

KW - chromatin domain

KW - CTCF boundary

KW - enhancer/promoter accessibility

KW - HOTTIP lncRNA

KW - HOTTIP transgenic mice

KW - HOX and hematopoietic gene regulation

KW - HSC self-renewal

KW - leukemia

KW - WNT signaling targets

UR - http://www.scopus.com/inward/record.url?scp=85075878690&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2019.10.011

DO - 10.1016/j.ccell.2019.10.011

M3 - Article

C2 - 31786140

AN - SCOPUS:85075878690

SN - 1535-6108

VL - 36

SP - 645-659.E8

JO - CANCER CELL

JF - CANCER CELL

IS - 6

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this