期刊
CANCER CELL
卷 36, 期 6, 页码 645-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2019.10.011
关键词
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资金
- National Institutes of Health [R01DK110108, R01CA204044, HL141950, R01CA172408, R01HL145883, R01HL141950, R01HL144712, R01HG007538, R01CA228140]
- Cancer Research UK
- Bloodwise
- San Antonio Cancer Council
- Four Diamonds Fund
- MRC [G0800892] Funding Source: UKRI
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.
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