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Differentiation block in acute myeloid leukemia regulated by intronic sequences of FTO
Camera, Francesco Romero-Camarero, Isabel Revell, Bradley H Amaral, Fabio M R Sinclair, Oliver J Simeoni, Fabrizio Wiseman, Daniel H. Stojic, L. Somervaille, Tim C P
Camera, Francesco
Romero-Camarero, Isabel
Revell, Bradley H
Amaral, Fabio M R
Sinclair, Oliver J
Simeoni, Fabrizio
Wiseman, Daniel H.
Stojic, L.
Somervaille, Tim C P
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Abstract
Iroquois transcription factor gene IRX3 is highly expressed in 20-30% of acute myeloid leukemia (AML) and contributes to the pathognomonic differentiation block. Intron 8 FTO sequences ∼220kB downstream of IRX3 exhibit histone acetylation, DNA methylation, and contacts with the IRX3 promoter, which correlate with IRX3 expression. Deletion of these intronic elements confirms a role in positively regulating IRX3. RNAseq revealed long non-coding (lnc) transcripts arising from this locus. FTO-lncAML knockdown (KD) induced differentiation of AML cells, loss of clonogenic activity, and reduced FTO intron 8:IRX3 promoter contacts. While both FTO-lncAML KD and IRX3 KD induced differentiation, FTO-lncAML but not IRX3 KD led to HOXA downregulation suggesting transcript activity in trans. FTO-lncAMLhigh AML samples expressed higher levels of HOXA and lower levels of differentiation genes. Thus, a regulatory module in FTO intron 8 consisting of clustered enhancer elements and a long non-coding RNA is active in human AML, impeding myeloid differentiation
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Date
2023
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Article
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Camera F, Romero-Camarero I, Revell BH, Amaral FMR, Sinclair OJ, Simeoni F, et al. Differentiation block in acute myeloid leukemia regulated by intronic sequences of FTO. iScience. 2023 Aug 18;26(8):107319. PubMed PMID: 37539037. Pubmed Central PMCID: PMC10393733. Epub 2023/08/04. eng.