Overexpression of CEBPA resulting from the translocation t(14;19)(q32;q13) of human precursor B acute lymphoblastic leukemia

Abstract

Subtle variation in the expression or function of a small group of transcription factors can drive leukemogenesis. The CEBPA protein is known to regulate the balance between cell proliferation and differentiation during early hematopoietic development and myeloid differentiation. In human myeloid leukemia, CEBPA is frequently inactivated by mutation and indirect and posttranslational mechanisms, in keeping with tumor suppressor properties. We report that CEBPA is activated by juxtaposition to the immunoglobulin gene enhancer upon its rearrangement with the immunoglobulin heavy-chain locus in precursor B-cell acute lymphoblastic leukemia harboring t(14;19)(q32;q13). Overexpression of apparently normal CEBPA RNA or protein was observed in 6 patients. These data indicate that CEBPA may exhibit oncogenic as well as tumor suppressor properties in human leukemogenesis. (Blood.

Transcriptional dysregulation during myeloid transformation in AML

“…Rather, the tumor suppressor function of CEBPA was based on observations of dominantnegative mutations and suppression of CEBPA expression in AML. This view was challenged by two recent reports indicating that five members of the CEBP transcription factor family are targeted by recurrent IGH-translocations in B-cell precursor acute lymphoblastic leukemia (B-ALL) (Chapiro et al, 2006;Akasaka et al, 2007). Remarkably, such translocations resulted in overexpression of affected CEBPs, including translocations t(14;19)(q32;q13) involving CEBPA.…”

Sumoylation and the function of CCAAT enhancer binding protein alpha (C/EBPα)

“…Here activation of C/EBPα is thought to result from the juxtaposition of the immunoglobin gene enhancer upstream of the C/EBPα gene [19]. Together these data suggest that increasing or decreasing the level of C/EBPα expression can contribute to leukemogenesis.…”

A novel translocation, t(14;19)(q32;p13), involving IGH@ and the cytokine receptor for erythropoietin

“…The use of the immunostimulatory CpGoligonucleotide DSP30 to effectively induce cell cycle progression of CLL cells in vitro has been reported. [3][4][5][6] This proliferation is markedly enhanced upon the addition of interleukin-2 to cultures. 4,7 Recently, Haferlach et al 5 characterized 506 CLL stimulated with DSP30 þ IL-2.…”

“…[2][3][4] In most cases, IGH@ translocations result in the transcriptional activation of an oncogene. 1 We report here a reciprocal translocation, t(14;19)(q32;p13), that juxtaposes the erythropoietin receptor precursor (EPOR) at 19p13 to the IGH@ enhancer resulting in its overexpression.…”