Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
CCAAT enhancer-binding protein (CEBP) transcription factors play pivotal roles in proliferation and differentiation, including suppression of myeloid leukemogenesis. Mutations of CEBPA are found in a subset of acute myeloid leukemia (AML) and in some cases of familial AML. Here, using cytogenetics, fluorescence in situ hybridization (FISH), and molecular cloning, we show that 5 CEBP gene family members are targeted by recurrent IGH chromosomal translocations in BCP-ALL. Ten patients with t(8;14)(q11;q32) involved CEBPD on chromosome 8, and 9 patients with t(14;19)(q32;q13) involved CEBPA, while a further patient involved CEBPG, located 71 kb telomeric of CEBPA in chromosome band 19q13; 4 patients with inv(14)(q11q32)/t(14;14)(q11;q32) involved CEBPE and 3 patients with t(14;20)(q32;q13) involved CEBPB. In 16 patients the translocation breakpoints were cloned using long-distance inverse-polymerase chain reaction (LDI-PCR). With the exception of CEBPD breakpoints, which were scattered within a 43-kb region centromeric of CEBPD, translocation breakpoints were clustered immediately 5' or 3' of the involved CEBP gene. Except in 1 patient with t(14;14)(q11;q32), the involved CEBP genes retained germ-line sequences. Quantitative reverse transcription (RT)-PCR showed overexpression of the translocated CEBP gene. Our findings implicate the CEBP gene family as novel oncogenes in BCP-ALL, and suggest opposing functions of CEBP dysregulation in myeloid and lymphoid leukemogenesis.
Akasaka
Takashi
T
Toxicology Unit, Medical Research Council, University of Leicester, Lancaster Road, Leicester, UK.
Balasas
Theodore
T
Russell
Lisa J
LJ
Sugimoto
Kei-ji
KJ
Majid
Aneela
A
Walewska
Renata
R
Karran
E Loraine
EL
Brown
David G
DG
Cain
Kelvin
K
Harder
Lana
L
Gesk
Stefan
S
Martin-Subero
Jose Ignacio
JI
Atherton
Mark G
MG
Brüggemann
Monika
M
Calasanz
María José
MJ
Davies
Teresa
T
Haas
Oskar A
OA
Hagemeijer
Anne
A
Kempski
Helena
H
Lessard
Michel
M
Lillington
Debra M
DM
Moore
Sarah
S
Nguyen-Khac
Florence
F
Radford-Weiss
Isabelle
I
Schoch
Claudia
C
Struski
Stéphanie
S
Talley
Polly
P
Welham
Melanie J
MJ
Worley
Helen
H
Strefford
Jon C
JC
Harrison
Christine J
CJ
Siebert
Reiner
R
Dyer
Martin J S
MJ
D002051:Burkitt Lymphoma / Q000235:genetics*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D002503:Centromere / Q000235:genetics; D002877:Chromosomes, Human / Q000235:genetics*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D005810:Multigene Family / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics*; D016133:Polymerase Chain Reaction; D016615:Telomere / Q000235:genetics; D014178:Translocation, Genetic
D022762:CCAAT-Enhancer-Binding Proteins; D007143:Immunoglobulin Heavy Chains