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

Publication date: Available online 27 November 2019Source: Cancer CellAuthor(s): 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 HuangSummaryLong 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.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research