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

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HOTTIP lncRNA Promotes Hematopoietic Stem Cell Self-Renewal Leading to AML-like Disease in Mice.
Cancer Cell ( IF 48.8 ) Pub Date : 2019-11-27 , DOI: 10.1016/j.ccell.2019.10.011
Huacheng Luo ₁ , Ganqian Zhu ₂ , Jianfeng Xu ₃ , Qian Lai ₄ , Bowen Yan ₅ , Ying Guo ₆ , Tsz Kan Fung ₇ , Bernd B Zeisig ₇ , Ya Cui ₈ , Jie Zha ₉ , Christopher Cogle ₁₀ , Fei Wang ₁₁ , Bing Xu ₉ , Feng-Chun Yang ₁₂ , Wei Li ₈ , Chi Wai Eric So ₇ , Yi Qiu ₅ , Mingjiang Xu ₁₃ , Suming Huang ₁₄

Affiliation

Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
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.
Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
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.
Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
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.
School of Cancer and Pharmaceutical Science, King's College London, London SE5 9NU, UK.
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.
Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
Division of Hematology/Oncology, Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Department of Hematology and Oncology, The Affiliated Zhongda Hospital, Southeast University Medical School, Nanjing 210009, China.
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.
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.
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.

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.

中文翻译：

HOTTIP lncRNA 促进造血干细胞自我更新，导致小鼠出现 AML 样疾病。

长非编码 RNA (lncRNA) 对于调节 HOX 基因至关重要，HOX 基因的畸变是白血病转化的主要机制。 HOX 基因相关的 lncRNA 如何调节造血干细胞 (HSC) 功能并促进白血病发生仍然是个谜。我们发现 HOTTIP 在急性髓系白血病 (AML) 中异常激活，从而改变 HOXA 驱动的拓扑相关结构域 (TAD) 和基因表达。 HOTTIP 丢失减弱了移植小鼠的白血病发生，而 HOTTIP 的重新激活则恢复了 CTCF 边界减弱的 AML 细胞中的白血病 TAD、转录和白血病发生。小鼠中的 Hottip 畸变通过改变同源/造血基因相关染色质特征和转录程序，异常促进 HSC 自我更新，导致 AML 样疾病。 Hottip 畸变作为一种致癌事件，通过重新编程白血病相关染色质和基因转录来扰乱 HSC 功能。

更新日期：2019-11-28

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