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.
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CTCF Boundary Remodels Chromatin Domain and Drives Aberrant HOX Gene Transcription in Acute Myeloid LeukemiaH Luo et al. Blood 132 (8), 837-848. PMID 29760161.HOX gene dysregulation is a common feature of acute myeloid leukemia (AML). The molecular mechanisms underlying aberrant HOX gene expression and associated …
Persistent Transactivation by meis1 Replaces Hox Function in Myeloid Leukemogenesis Models: Evidence for Co-Occupancy of meis1-pbx and Hox-Pbx Complexes on Promoters of Leukemia-Associated GenesGG Wang et al. Mol Cell Biol 26 (10), 3902-16. PMID 16648484.Homeobox transcription factors Meis1 and Hoxa9 promote hematopoietic progenitor self-renewal and cooperate to cause acute myeloid leukemia (AML). While Hoxa9 alone blocks …
LncRNA HOTTIP Promotes Proliferation and Cell Cycle Progression of Acute Myeloid Leukemia CellsMF Zhuang et al. Eur Rev Med Pharmacol Sci 23 (7), 2908-2915. PMID 31002141.HOTTIP accelerated the proliferative ability and cell cycle of AML cells via up-regulating DDA1 expression by sponging microRNA-608.
Ecotropic Viral Integration Site 1, Stem Cell Self-Renewal and LeukemogenesisK Kataoka et al. Cancer Sci 103 (8), 1371-7. PMID 22494115. - ReviewIt has become evident that acute myeloid leukemia (AML) is organized as a cellular hierarchy initiated and maintained by a subset of self-renewing leukemia stem cells. Re …
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