A Appert

A Bohne

AA Ferrando

AJ Warren

B Gottgens

B Göttgens

B J Huntly

B Royer-Pokora

BD MacArthur

C Pridans

CD Baldus

EA Kruse

EJ Yeoh

GA Follows

H Osada

IA Wadman

IJ Donaldson

J -R Landry

J A I Thoms

J E Pimanda

JE Pimanda

JL Kadrmas

JR Landry

M E Janes

M van Grotel

MP McCormack

NK Wilson

P -S Jayaraman

P Noy

R B Lock

R Garand

RB Lock

RC Larson

S Anand

S Chiaretti

S H Oram

S Hacein-Bey-Abina

S J Kinston

SC Crable

SC Raimondi

SJ Howe

SM Hammond

T Boehm

TH Rabbitts

UP Dave

V Asnafi

V Valge-Archer

WM Crist

WY Chan

X Huang

Y Yamada

The T-cell oncogene Lim-only 2 (LMO2) critically influences both normal and malignant haematopoiesis. LMO2 is not normally expressed in T cells, yet ectopic expression is seen in the majority of T-acute lymphoblastic leukaemia (T-ALL) patients with specific translocations involving LMO2 in only a subset of these patients. Ectopic lmo2 expression in thymocytes of transgenic mice causes T-ALL, and retroviral vector integration into the LMO2 locus was implicated in the development of clonal T-cell disease in patients undergoing gene therapy. Using array-based chromatin immunoprecipitation, we now demonstrate that in contrast to B-acute lymphoblastic leukaemia, human T-ALL samples largely use promoter elements with little influence from distal enhancers. Active LMO2 promoter elements in T-ALL included a previously unrecognized third promoter, which we demonstrate to be active in cell lines, primary T-ALL patients and transgenic mice. The ETS factors ERG and FLI1 previously implicated in lmo2-dependent mouse models of T-ALL bind to the novel LMO2 promoter in human T-ALL samples, while in return LMO2 binds to blood stem/progenitor enhancers in the FLI1 and ERG gene loci. Moreover, LMO2, ERG and FLI1 all regulate the +1 enhancer of HHEX/PRH, which was recently implicated as a key mediator of early progenitor expansion in LMO2-driven T-ALL. Our data therefore suggest that a self-sustaining triad of LMO2/ERG/FLI1 stabilizes the expression of important mediators of the leukaemic phenotype such as HHEX/PRH

Oram, SH

Thoms, JA

Pridans, Clare

Janes, ME

Kinston, SJ

Anand, S

Landry, JR

Lock, RB

Jayaraman, PS

Huntly, BJP

Pimanda, JE

Gottgens, B

Edinburgh Research Explorer

A previously unrecognized promoter of LMO2 forms part of a transcriptional regulatory circuit mediating LMO2 expression in a subset of T-acute lymphoblastic leukaemia patients

A previously unrecognized promoter of LMO2 forms part of a transcriptional regulatory circuit mediating LMO2 expression in a subset of T-acute lymphoblastic leukaemia patients

Abstract

Similar works

Full text

Available Versions

Edinburgh Research Explorer

University of Birmingham Research Portal

University of Birmingham Research Portal

Crossref