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

Cancer Cell. 2019 Dec 9;36(6):645-659.e8. doi: 10.1016/j.ccell.2019.10.011. Epub 2019 Nov 27.


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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / genetics
  • Cell Self Renewal / genetics*
  • Chromatin / metabolism
  • Gene Expression Regulation, Leukemic / genetics*
  • Gene Knockdown Techniques / methods
  • Hematopoietic Stem Cells / metabolism
  • Homeodomain Proteins / genetics
  • Leukemia, Myeloid, Acute / genetics*
  • Mice
  • RNA, Long Noncoding / genetics*


  • Chromatin
  • Homeodomain Proteins
  • RNA, Long Noncoding
  • long noncoding RNA HOTTIP, human