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

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. [Display omitted] •HOTTIP reprograms 3D AML genome and drives leukemic transcription profile in AML•HOTTIP binds and regulates genes important for hematopoiesis and leukemogenesis•HOTTIP KO attenuates AML progression by impairing leukemic transcription program•Hottip aberration perturbs HSC self-renewal leading to AML-like disease in mice Luo et al. find that the lncRNA HOTTIP is overexpressed in acute myeloid leukemia (AML). They show that HOTTIP coordinates topologically associated domain organization in the AML genome, including the posterior HOXA genes and various key hematopoietic regulator loci, and is important for AML growth.