AML1/ETO Downregulates the Transcription Factor PU.1 in Acute Myeloid Leukemia

AML1-ETO is a fusion protein encoded by the translocation t(8;21)
and found in 15% of acute myeloid leukemia patients. Here, we
report a negative functional impact of AML1-ETO on the
transcriptional activity of PU.1, an important transcription factor
for normal myeloid differentiation. We have demonstrated that
AML1-ETO interacts with PU.1 by immunoprecipitation assay in
Kasumi-1 cells having t(8;21). On mapping the region of interaction
in PU.1, we found that AML1-ETO binds to the b3b4 region in the DNA
binding domain of PU.1 and displaces the co-activator c-Jun from
PU.1, thus downregulating PU.1’s transcriptional activity. In doing
so AML1-ETO does not change the DNA binding capacity of PU.1. The
expression levels of PU.1 target genes in acute myeloid leukemia
(AML)-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 PU.1 induced differentiation
in HL60 cells. Overexpression of PU.1 differentiates AML1-ETO
carrying Kasumi-1 cells to the monocytic lineage. Thus, PU.1’s
function is downregulated in presence of AML1-ETO in acute myeloid
leukemia, whereas overexpression of PU.1 can restore normal
differentiation.