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Analyzing the oncogenic role of the hematopoietic transcription factor PU.1

English title Analyzing the oncogenic role of the hematopoietic transcription factor PU.1
Applicant Tschan Mario P.
Number 118276
Funding scheme Project funding (Div. I-III)
Research institution Department for BioMedical Research Universität Bern
Institution of higher education University of Berne - BE
Main discipline Experimental Cancer Research
Start/End 01.10.2007 - 30.04.2010
Approved amount 173'300.00
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All Disciplines (3)

Discipline
Experimental Cancer Research
Cellular Biology, Cytology
Molecular Biology

Keywords (6)

Leukemia; hematopoiesis; oncogene; PU.1; p53; p73

Lay Summary (English)

Lead
Lay summary
Transcription factors play a major role in lineage commitment and differentiation of hematopoietic stem cells and progenitors into distinct blood cell types. A key player in blood development is the hematopoietic-specific transcriptional activator PU.1, which is encoded by the gene Sfpi1. Evidence from PU.1 knockout mice indicates that PU.1 is absolutely required for the differentiation of myeloid-lineage cells and B lymphocytes. Interestingly, the PU.1 protein is also directly involved in the pathogenesis of human leukemias. It was originally identified as a product of the Spi-1 (SFFV proviral integration-1) proto-oncogene, whose locus serves as a high-frequency integration site for the spleen focus-forming virus (SFFV) associated with high PU.1 expression in murine erythroleukemias. Likewise, reduced PU.1 levels in mice lead to acute myeloid leukemias (AML). Moreover, both AML1/ETO and FLT3-ITD leukemic oncogenes inhibit PU.1 activity, therefore reinforcing the notion that reduced PU.1 function may contribute to AML.These data highlight the versatility of this transcription factor in promoting or preventing differentiation depending on the hematopoietic lineage and the stage of development. Generally, the role of PU.1 in terminal differentiation of myeloid and lymphoid cells has been extensively studied, whereas mechanisms responsible for the proliferation of hematopoietic precursors and the role of PU.1 as oncogene are still partially unclear. Interestingly, we have recently observed that PU.1 binds to the p53 tumor suppressor family and inhibits their transcriptional activity. Moreover, we identified novel putative PU.1 target genes involved in proliferation and survival of hematopoietic cells using DNA microarray analysis of mouse fetal liver derived PU.1 knock-out cells. We hypothesize that aberrant PU.1 expression contributes to a growth and survival advantage via inhibiting the p53 family of transcription factors and/or by regulating the newly identified PU.1 transcriptional targets involved in cell cycle or survival.To support our hypothesis that PU.1 inhibits p53 transcriptional activity, we will evaluate the expression of known p53/73 targets in PU.1 knockout cells and study cell proliferation and activation of p53/73 targets in erythroleukemia cells upon PU.1 knockdown using RNA interference. In addition, we will analyze the molecular mechanisms underlying the transcriptional repression of p53 by PU.1. Lastly, we will evaluate the newly proposed PU.1 transcriptional targets involved in cell survival and growth during hematopoietic differentiation.PU.1 is a master regulator of myeloid development, and the analysis of its role in governing not only hematopoietic differentiation but also cell survival, stemness and proliferation is central to an understanding of the normal and cancerous myeloid differentiation program. The proposed studies will elucidate mechanisms leading to tumor development, a prerequisite for effective therapy designs.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
129955 Complex involvement of the myeloid master gene PU.1 in cell proliferation and survival by inhibiting the p53 tumor suppressor pathway and by activating anti-apoptotic genes 01.04.2010 Project funding (Div. I-III)

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