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

Francesco Camera; Isabel Romero-Camarero; Bradley H Revell; Fabio M R Amaral; Oliver J Sinclair; Fabrizio Simeoni; Daniel H Wiseman; Lovorka Stojic; Tim C P Somervaille

doi:10.1016/j.isci.2023.107319

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

iScience. 2023 Jul 11;26(8):107319. doi: 10.1016/j.isci.2023.107319. eCollection 2023 Aug 18.

Authors

Francesco Camera¹, Isabel Romero-Camarero¹, Bradley H Revell¹, Fabio M R Amaral¹, Oliver J Sinclair¹, Fabrizio Simeoni¹, Daniel H Wiseman², Lovorka Stojic³, Tim C P Somervaille¹

Affiliations

¹ Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, The Oglesby Cancer Research Centre Building, 555 Wilmslow Road, M20 4GJ Manchester, UK.
² Epigenetics of Haematopoiesis Group, Oglesby Cancer Research Building, The University of Manchester, M20 4GJ Manchester, UK.
³ Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, EC1M 6BQ London, UK.

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-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.

Keywords: Cancer; Epigenetics; Molecular mechanism of gene regulation; Transcriptomics.