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Differentiation block in acute myeloid leukemia regulated by intronic sequences of FTO

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...

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Autores principales: Camera, Francesco, Romero-Camarero, Isabel, Revell, Bradley H., Amaral, Fabio M.R., Sinclair, Oliver J., Simeoni, Fabrizio, Wiseman, Daniel H., Stojic, Lovorka, Somervaille, Tim C.P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393733/
https://www.ncbi.nlm.nih.gov/pubmed/37539037
http://dx.doi.org/10.1016/j.isci.2023.107319
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author Camera, Francesco
Romero-Camarero, Isabel
Revell, Bradley H.
Amaral, Fabio M.R.
Sinclair, Oliver J.
Simeoni, Fabrizio
Wiseman, Daniel H.
Stojic, Lovorka
Somervaille, Tim C.P.
author_facet Camera, Francesco
Romero-Camarero, Isabel
Revell, Bradley H.
Amaral, Fabio M.R.
Sinclair, Oliver J.
Simeoni, Fabrizio
Wiseman, Daniel H.
Stojic, Lovorka
Somervaille, Tim C.P.
author_sort Camera, Francesco
collection PubMed
description 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-lncAML(high) 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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spelling pubmed-103937332023-08-03 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, Lovorka Somervaille, Tim C.P. iScience Article 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-lncAML(high) 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. Elsevier 2023-07-11 /pmc/articles/PMC10393733/ /pubmed/37539037 http://dx.doi.org/10.1016/j.isci.2023.107319 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Camera, Francesco
Romero-Camarero, Isabel
Revell, Bradley H.
Amaral, Fabio M.R.
Sinclair, Oliver J.
Simeoni, Fabrizio
Wiseman, Daniel H.
Stojic, Lovorka
Somervaille, Tim C.P.
Differentiation block in acute myeloid leukemia regulated by intronic sequences of FTO
title Differentiation block in acute myeloid leukemia regulated by intronic sequences of FTO
title_full Differentiation block in acute myeloid leukemia regulated by intronic sequences of FTO
title_fullStr Differentiation block in acute myeloid leukemia regulated by intronic sequences of FTO
title_full_unstemmed Differentiation block in acute myeloid leukemia regulated by intronic sequences of FTO
title_short Differentiation block in acute myeloid leukemia regulated by intronic sequences of FTO
title_sort differentiation block in acute myeloid leukemia regulated by intronic sequences of fto
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393733/
https://www.ncbi.nlm.nih.gov/pubmed/37539037
http://dx.doi.org/10.1016/j.isci.2023.107319
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