Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL)

Akasaka, Takashi; Balasas, Theodore; Russell, Lisa J; Sugimoto, Kei-ji; Majid, Aneela; Walewska, Renata; Karran, E Loraine; Brown, David G; Cain, Kelvin; Harder, Lana; Gesk, Stefan; Martin-Subero, Jose Ignacio; Atherton, Mark G; Brüggemann, Monika; Calasanz, María José; Davies, Teresa; Haas, Oskar A; Hagemeijer-Hausman, Anne; Kempski, Helena; Lessard, Michel; Lillington, Debra M; Moore, Sarah; Nguyen-Khac, Florence; Radford-Weiss, Isabelle; Schoch, Claudia; Struski, Stéphanie; Talley, Polly; Welham, Melanie J; Worley, Helen; Strefford, Jon C; Harrison, Christine J; Siebert, Reiner; Dyer, Martin JS

doi:10.1182/blood-2006-08-041012

Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL)

Author:

Akasaka, Takashi

Balasas, Theodore ; Russell, Lisa J ; Sugimoto, Kei-ji ; Majid, Aneela ; Walewska, Renata ; Karran, E Loraine ; Brown, David G ; Cain, Kelvin ; Harder, Lana ; Gesk, Stefan ; Martin-Subero, Jose Ignacio ; Atherton, Mark G ; Brüggemann, Monika ; Calasanz, María José ; Davies, Teresa ; Haas, Oskar A ; Hagemeijer-Hausman, Anne ; Kempski, Helena ; Lessard, Michel ; Lillington, Debra M ; Moore, Sarah ; Nguyen-Khac, Florence ; Radford-Weiss, Isabelle ; Schoch, Claudia ; Struski, Stéphanie ; Talley, Polly ; Welham, Melanie J ; Worley, Helen ; Strefford, Jon C ; Harrison, Christine J ; Siebert, Reiner ; Dyer, Martin JS

Keywords:

Burkitt Lymphoma, CCAAT-Enhancer-Binding Proteins, Centromere, Chromosomes, Human, Humans, Immunoglobulin Heavy Chains, In Situ Hybridization, Fluorescence, Multigene Family, Oncogenes, Polymerase Chain Reaction, Telomere, Translocation, Genetic, Science & Technology, Life Sciences & Biomedicine, Hematology, ACUTE MYELOID-LEUKEMIA, BINDING-PROTEIN-EPSILON, POLYMERASE-CHAIN-REACTION, ALPHA C/EBP-ALPHA, GRANULOCYTIC DIFFERENTIATION, CHROMOSOMAL TRANSLOCATION, GRANULE DEFICIENCY, MOLECULAR-CLONING, FUSION GENE, MUTATIONS, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, 1114 Paediatrics and Reproductive Medicine, Immunology, 3101 Biochemistry and cell biology, 3201 Cardiovascular medicine and haematology, 3213 Paediatrics

Abstract:

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.