Distinct poor prognostic subgroups of acute myeloid leukaemia, FLT3-ITD and P-glycoprotein-positive, have contrasting levels of FOXO1

Claire H Seedhouse; Ken I Mills; Sophie Ahluwalia; Martin Grundy; Shili Shang; Alan K Burnett; Nigel H Russell; Monica Pallis

doi:10.1016/j.leukres.2013.10.030

Distinct poor prognostic subgroups of acute myeloid leukaemia, FLT3-ITD and P-glycoprotein-positive, have contrasting levels of FOXO1

Leuk Res. 2014 Jan;38(1):131-7. doi: 10.1016/j.leukres.2013.10.030. Epub 2013 Nov 8.

Authors

Claire H Seedhouse¹, Ken I Mills², Sophie Ahluwalia³, Martin Grundy⁴, Shili Shang³, Alan K Burnett⁵, Nigel H Russell⁴, Monica Pallis⁶

Affiliations

¹ Department of Haematology, University of Nottingham, Nottingham, UK. Electronic address: claire.seedhouse@nottingham.ac.uk.
² Centre for Cancer Research and Cell Biology (CCRCB), Queen's University Belfast, Belfast, UK.
³ Department of Haematology, University of Nottingham, Nottingham, UK.
⁴ Department of Haematology, University of Nottingham, Nottingham, UK; Clinical Haematology, Nottingham University Hospitals, Nottingham, UK.
⁵ Department of Haematology, Cardiff University, Cardiff, UK.
⁶ Clinical Haematology, Nottingham University Hospitals, Nottingham, UK.

PMID: 24268349
DOI: 10.1016/j.leukres.2013.10.030

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).

Keywords: ABCB1; AML; FLT3-ITD; FOXO1; p-glycoprotein.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Acute Disease
Adult
Blotting, Western
Cell Line, Tumor
Flow Cytometry
Forkhead Box Protein O1
Forkhead Transcription Factors / genetics*
Forkhead Transcription Factors / metabolism
Gene Expression Regulation, Leukemic
HL-60 Cells
Humans
Leukemia, Myeloid / genetics*
Leukemia, Myeloid / metabolism
Leukemia, Myeloid / pathology
Leukocyte Count
Mutation
Oligonucleotide Array Sequence Analysis
Prognosis
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Tandem Repeat Sequences
Transcriptome
fms-Like Tyrosine Kinase 3 / genetics*
fms-Like Tyrosine Kinase 3 / metabolism

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
FOXO1 protein, human
Forkhead Box Protein O1
Forkhead Transcription Factors
FLT3 protein, human
fms-Like Tyrosine Kinase 3