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, 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 and Dyer, Martin J.S. (2007) Five members of the CEBP transcription factor family are targeted by recurrent IGH-translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blood, 109 (8), 3451-3461. (doi:10.1182/blood-2006-08-041012).

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.

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Contributors

Author: Helen Worley

Author: Jon C. Strefford

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