title: Distinct poor prognostic subgroups of acute myeloid leukaemia, FLT3-ITD and P-glycoprotein-positive, have contrasting levels of FOXO1.
abstract: Regulation of ABCB1 (P-glycoprotein/Pgp) in AML was investigated. In a historical cohort with Pgp and transcriptional regulator expression profiling data available (n=141), FOXO1 correlated with Pgp protein expression. This was confirmed in an independent cohort (n=204). Down-regulation (siRNA) or hyperactivation (nicotinamide) of FOXO1 led to corresponding changes in Pgp. Low FOXO1 expression correlated with FLT3-ITDs (p<0.001) and siRNA inhibition of FLT3-ITD up-regulated FOXO1. As FOXO1 is a key growth regulator, it may underpin biological differences between Pgp-positive clones (low WBC and primary resistant disease) and clones with a FLT3-ITD (associated with a high WBC and early relapse).
authors.affiliation: Department of Haematology, University of Nottingham, Nottingham, UK. Electronic address: claire.seedhouse@nottingham.ac.uk.
authors.forename: Claire H
authors.initials: CH
authors.lastname: Seedhouse
authors.affiliation: Centre for Cancer Research and Cell Biology (CCRCB), Queen's University Belfast, Belfast, UK.
authors.forename: Ken I
authors.initials: KI
authors.lastname: Mills
authors.affiliation: Department of Haematology, University of Nottingham, Nottingham, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Ahluwalia
authors.affiliation: Department of Haematology, University of Nottingham, Nottingham, UK; Clinical Haematology, Nottingham University Hospitals, Nottingham, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Grundy
authors.affiliation: Department of Haematology, University of Nottingham, Nottingham, UK.
authors.forename: Shili
authors.initials: S
authors.lastname: Shang
authors.affiliation: Department of Haematology, Cardiff University, Cardiff, UK.
authors.forename: Alan K
authors.initials: AK
authors.lastname: Burnett
authors.affiliation: Department of Haematology, University of Nottingham, Nottingham, UK; Clinical Haematology, Nottingham University Hospitals, Nottingham, UK.
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Russell
authors.affiliation: Clinical Haematology, Nottingham University Hospitals, Nottingham, UK.
authors.forename: Monica
authors.initials: M
authors.lastname: Pallis
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000208:Acute Disease; D000328:Adult; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007958:Leukocyte Count; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020080:Tandem Repeat Sequences; D059467:Transcriptome; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: ABCB1; AML; FLT3-ITD; FOXO1; p-glycoprotein