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Prepublished online as a Blood First Edition Paper on September 12, 2002; DOI 10.1182/blood-2002-04-1207.
Submitted April 22, 2002
Accepted September 3, 2002
The gene encoding the transcriptional regulator Yin Yang 1(YY1) is a myeloid transforming gene interfering with neutrophilic differentiation
Stefan J Erkeland, Marijke Valkhof, Claudia Heijmans-Antonissen, Ruud Delwel, Peter J M Valk, Mirjam H Hermans, and Ivo P Touw*
Institute of Hematology, Erasmus University Rotterdam, Rotterdam, The Netherlands
* Corresponding author; email: touw{at}hema.fgg.eur.nl.
The genetic defects underlying the pathogenesis of acute myeloid leukemia (AML) are still largely unknown. Retroviral insertion mutagenesis in mice has become a powerful tool to identify candidate genes involved in the development of leukemia and lymphoma. We have employed this strategy using the 1.4 strain of Graffi murine leukemia virus (MuLV), which predominantly causes myeloid leukemias. Here, we report that Graffi-1.4-induced AML frequently harbors virus integrations in the gene encoding the transcription factor Yin Yang 1 (YY1). These integrations occurred in both orientations and were all located in the 5' promoter region of the gene, 0.5 to 1.5 kb upstream of the major transcriptional start site. Luciferase reporter assays showed that virus integration in this region increases promoter activity, and renders it independent of a functional binding site for Sp1, a major transcriptional regulator of YY1. We employed the murine 32D model to study the consequence of perturbed YY1 expression for myelopoiesis. YY1 protein levels were high in 32D parental cells maintained in interleukin-3-containing medium, but dropped when the cells were induced to differentiate by granulocyte colony-stimulating factor (G-CSF). Strikingly, G-CSF-induced neutrophilic differentiation was reduced in 32D cell transfectants ectopically expressing YY1. In similar experiments on primary bone marrow cells, enforced YY1 expression blocked the outgrowth of CFU-GM colonies. Increased YY1 expression was seen in some cases of human AML. Collectively, these data imply a possible role of perturbed expression of YY1 in the development of AML, by interfering with the myeloid differentiation program in the leukemic progenitor cells.
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