PMID- 37539037
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230805
IS  - 2589-0042 (Electronic)
IS  - 2589-0042 (Linking)
VI  - 26
IP  - 8
DP  - 2023 Aug 18
TI  - Differentiation block in acute myeloid leukemia regulated by intronic sequences 
      of FTO.
PG  - 107319
LID - 10.1016/j.isci.2023.107319 [doi]
LID - 107319
AB  - 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  approximately 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.
CI  - (c) 2023 The Authors.
FAU - Camera, Francesco
AU  - Camera F
AD  - 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.
FAU - Romero-Camarero, Isabel
AU  - Romero-Camarero I
AD  - 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.
FAU - Revell, Bradley H
AU  - Revell BH
AD  - 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.
FAU - Amaral, Fabio M R
AU  - Amaral FMR
AD  - 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.
FAU - Sinclair, Oliver J
AU  - Sinclair OJ
AD  - 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.
FAU - Simeoni, Fabrizio
AU  - Simeoni F
AD  - 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.
FAU - Wiseman, Daniel H
AU  - Wiseman DH
AD  - Epigenetics of Haematopoiesis Group, Oglesby Cancer Research Building, The 
      University of Manchester, M20 4GJ Manchester, UK.
FAU - Stojic, Lovorka
AU  - Stojic L
AD  - Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary 
      University of London, Charterhouse Square, EC1M 6BQ London, UK.
FAU - Somervaille, Tim C P
AU  - Somervaille TCP
AD  - 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.
LA  - eng
PT  - Journal Article
DEP - 20230711
PL  - United States
TA  - iScience
JT  - iScience
JID - 101724038
PMC - PMC10393733
OTO - NOTNLM
OT  - Cancer
OT  - Epigenetics
OT  - Molecular mechanism of gene regulation
OT  - Transcriptomics
COIS- All contributing authors declare that there is no conflict of interest with 
      regard to the data presented in this study.
EDAT- 2023/08/04 06:43
MHDA- 2023/08/04 06:44
PMCR- 2023/07/11
CRDT- 2023/08/04 04:09
PHST- 2023/01/31 00:00 [received]
PHST- 2023/05/23 00:00 [revised]
PHST- 2023/07/04 00:00 [accepted]
PHST- 2023/08/04 06:44 [medline]
PHST- 2023/08/04 06:43 [pubmed]
PHST- 2023/08/04 04:09 [entrez]
PHST- 2023/07/11 00:00 [pmc-release]
AID - S2589-0042(23)01396-2 [pii]
AID - 107319 [pii]
AID - 10.1016/j.isci.2023.107319 [doi]
PST - epublish
SO  - iScience. 2023 Jul 11;26(8):107319. doi: 10.1016/j.isci.2023.107319. eCollection 
      2023 Aug 18.