美国宾夕法尼亚州立大学医学院Suming Huang、得克萨斯大学圣安东尼奥健康科学中心Mingjiang Xu、佛罗里达大学医学院Yi Qiu以及伦敦国王学院癌症与药物科学学院Chi Wai Eric So研究组合作研究，发现HOTTIP 长的非编码RNA（lncRNA）促进造血干细胞（HSC）自我更新并导致小鼠类急性髓细胞性白血病（AML）疾病。

2019年11月27日，国际学术期刊《癌细胞》发表了这一成果。

他们发现HOTTIP在AML中被异常激活，以改变HOXA驱动的拓扑相关结构域（TAD）和基因表达。HOTTIP丢失会减弱移植小鼠的白血病发生，而HOTTIP的重新激活则可以恢复CTCF边界减弱的AML细胞中白血病TAD、转录和白血病发生。小鼠的Hottip畸变通过改变与同源异型/造血基因相关的染色质标签和转录程序，异常促进了HSC自我更新，导致类AML疾病。Hottip畸变是通过重新编程白血病相关的染色质和基因转录来扰动HSC功能的致癌事件。

据了解， lncRNA对于调节HOX基因至关重要，其畸变是白血病转化的主要机制。HOX基因相关的lncRNAs如何调节HSC的功能，并促进白血病的发生仍然是未知的。

附：英文原文

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

Author: 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

Issue&Volume: November 27, 2019

Abstract: Long non-coding RNAs (lncRNAs) are critical for regulating HOX genes, aberration ofwhich is a dominant mechanism for leukemic transformation. How HOX gene-associatedlncRNAs regulate hematopoietic stem cell (HSC) function and contribute to leukemogenesisremains elusive. We found that HOTTIP is aberrantly activated in acute myeloid leukemia (AML) to alter HOXA-driven topologicallyassociated 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-attenuatedAML cells. Hottip aberration in mice abnormally promotes HSC self-renewal leading to AML-like diseaseby altering the homeotic/hematopoietic gene-associated chromatin signature and transcriptionprogram. Hottip aberration acts as an oncogenic event to perturb HSC function by reprogramming leukemic-associatedchromatin and gene transcription.

DOI: 10.1016/j.ccell.2019.10.011

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30485-4