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Blood, 15 April 2007, Vol. 109, No. 8, pp. 3451-3461.
Prepublished online as a Blood First Edition Paper on December 14, 2006; DOI 10.1182/blood-2006-08-041012.
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NEOPLASIA
Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL)
Takashi Akasaka1,
Theodore Balasas1,
Lisa J. Russell2,
Kei-ji Sugimoto1,
Aneela Majid1,
Renata Walewska1,
E. Loraine Karran1,
David G. Brown1,
Kelvin Cain1,
Lana Harder3,
Stefan Gesk3,
Jose Ignacio Martin-Subero3,
Mark G. Atherton4,
Monika Brüggemann5,
María José Calasanz6,
Teresa Davies7,
Oskar A. Haas8,
Anne Hagemeijer9,
Helena Kempski10,
Michel Lessard11,
Debra M. Lillington12,
Sarah Moore13,
Florence Nguyen-Khac14,
Isabelle Radford-Weiss15,
Claudia Schoch16,
Stéphanie Struski11,
Polly Talley17,
Melanie J. Welham18,
Helen Worley2,
Jon C. Strefford2,
Christine J. Harrison2,
Reiner Siebert3, and
Martin J. S. Dyer1
1 Medical Research Council (MRC) Toxicology Unit, University of Leicester, United Kingdom;
2 Leukaemia Research Cytogenetics Group, Cancer Sciences Division, University of Southampton, United Kingdom;
3 Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel, Germany;
4 Merseyside & Cheshire Genetics Laboratory, Liverpool Women's Hospital, United Kingdom;
5 Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Germany;
6 Departamento de Genética, Universidad de Navarra, Pamplona, Spain;
7 South West Regional Cytogenetics Centre, Southmead Hospital, Bristol, United Kingdom;
8 Children's Cancer Research Institute, Vienna, Austria;
9 Center for Human Genetics, Leuven, Belgium;
10 Paediatric Malignancy Cytogenetics Laboratory, Great Ormond Street Hospital for Sick Children, London, United Kingdom;
11 Laboratoire d'Hématologie, Hôpital de Hautepierre, Strasbourg, France;
12 Cancer Research UK Medical Oncology Unit, St Bartholomew's Hospital Medical School, Queen Mary University of London, United Kingdom;
13 South Australia Cancer Cytogenetics Unit, Institute of Medical and Veterinary Science, Adelaide, Australia;
14 Unité de Cytogénétique Hématologique, EO210 Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Hospitalier Pitié-Salpetriere, Paris, France;
15 Unité de Cytogénétique Hématologique, Service d'Histo-Embryologie et de Cytogénétique, Hôpital Necker–Enfants Malades, Paris, France;
16 MLL Münchner Leukämielabor, Munich, Germany;
17 Sheffield Regional Cytogenetics Service, Sheffield Children's Hospital, United Kingdom;
18 Department of Pharmacy and Pharmacology, University of Bath, United Kingdom
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.
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