CARD10, a CEBPE target involved in granulocytic differentiation
HAEMATOLOGICA
Authors: Shyamsunder, Pavithra; Sankar, Haresh; Mayakonda, Anand; Han, Lin; Nordin, Hazimah Binte Mohd; Woon, Teoh Weoi; Shanmugasundaram, Mahalakshmi; Dakle, Pushkar; Madan, Vikas; Koeffler, H. Phillip
Abstract
Maturation of granulocytes is dependent on controlled gene expression by myeloid lineage restricted transcription factors. CEBPE is one of the essential transcription factors required for granulocytic differentiation. Identification of downstream targets of CEBPE is vital to understand better its role in terminal granulopoiesis. In this study, we have identified Card10 as a novel target of CEBPE. We show that CEBPE binds to regulatory elements upstream of the murine Card10 locus, and expression of CARD10 is significantly reduced in Cebpe knock-out mice. Silencing Card10 in a human cell line and in murine primary cells impaired granulopoiesis, affecting expression of genes involved in myeloid cell development and function. Taken together, our data demonstrate for the first time that Card10 is expressed in granulocytes and is a direct target of CEBPE with functions extending to myeloid differentiation.
Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL)
BLOOD
Authors: 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.; Brueggemann, Monika; Calasanz, Maria Jose; 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, Stephanie; Talley, Polly; Welham, Melanie J.; Worley, Helen; Strefford, Jon C.; Harrison, Christine J.; Siebert, Reiner; Dyer, Martin J. S.
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(l 4;1 4)(q11;q32), the involved CEBP genes retained germline 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.
COA
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