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Prepublished online as a Blood First Edition Paper on August 29, 2002; DOI 10.1182/blood-2002-04-1288.
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Blood, 1 January 2003, Vol. 101, No. 1, pp. 270-277
NEOPLASIA
The myeloid master regulator transcription factor PU.1 is
inactivated by AML1-ETO in t(8;21) myeloid leukemia
Rajani K. Vangala,
Marion
S. Heiss-Neumann,
Janki S. Rangatia,
Sheo M. Singh,
Claudia Schoch,
Daniel G. Tenen,
Wolfgang Hiddemann, and
Gerhard Behre
From the Department of Internal Medicine III,
University Hospital Grosshadern, Ludwig-Maximilians-University Munich
and GSF-National Research Center for Environment and Health, Munich,
Germany; and Harvard Institutes of Medicine, Harvard
Medical School, Boston, MA.
The transcription factor PU.1 plays a pivotal role in normal
myeloid differentiation. PU.1 / mice exhibit a complete
block in myeloid differentiation. Heterozygous PU.1 mutations were
reported in some patients with acute myeloid leukemia (AML), but not in
AML with translocation t(8;21), which gives rise to the fusion gene
AML1-ETO. Here we report a negative functional
impact of AML1-ETO on the transcriptional activity of PU.1. AML1-ETO
physically binds to PU.1 in t(8;21)+ Kasumi-1 cells.
AML1-ETO binds to the  34 region in the
DNA-binding domain of PU.1 and displaces the coactivator c-Jun from
PU.1, thus down-regulating the transcriptional activity of PU.1. This physical interaction of AML1-ETO and PU.1 did not abolish the DNA-binding capacity of PU.1. AML1-ETO down-regulates the
transactivation capacity of PU.1 in myeloid U937 cells, and the
expression levels of PU.1 target genes in AML French-American-British
(FAB) subtype M2 patients with t(8;21) were lower than in patients
without t(8;21). Conditional expression of AML1-ETO causes
proliferation in mouse bone marrow cells and inhibits antiproliferative
function of PU.1. Overexpression of PU.1, however, differentiates
AML1-ETO-expressing Kasumi-1 cells to the monocytic lineage. Thus, the
function of PU.1 is down-regulated by AML1-ETO in t(8;21) myeloid
leukemia, whereas overexpression of PU.1 restores normal differentiation.
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