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Prepublished online as a Blood First Edition Paper on September 12, 2002; DOI 10.1182/blood-2002-04-1207.
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Blood, 1 February 2003, Vol. 101, No. 3, pp. 1111-1117
NEOPLASIA
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. A. Hermans, and
Ivo P. Touw
From the Department of Hematology, Erasmus University
Medical Center, Rotterdam, The Netherlands.
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
used this strategy with 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 all were 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 used 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 they 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 through interference with the myeloid
differentiation program in the leukemic progenitor cells.
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