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.

Level thesis:degree_level

thesis.doctoral

Grantor dc:publisher

Ludwig-Maximilians-Universität

Year

2003

Author dc:creator

• Vangala, Rajani Kanth

Repository record source_url

https://edoc.ub.uni-muenchen.de/1027/

OAI identifier oai:identifier

oai:edoc.ub.uni-muenchen.de:1027