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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

English title 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
Applicant Tschan Mario P.
Number 129955
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 01.04.2010 - 31.12.2012
Approved amount 250'000.00
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All Disciplines (3)

Discipline
Experimental Cancer Research
Immunology, Immunopathology
Cellular Biology, Cytology

Keywords (9)

PU.1; p53 family of tumor suppressors; Acute Myeloid Leukemia; Erythroleukemia; Myeloid differentiation; Chemoresistance; Spi-1; oncogene p53, p73; transcriptional regulation

Lay Summary (English)

Lead
Lay summary
A hallmark of acute myeloid leukemia (AML) is an impairment of normal blood cell differentiation leading to an accumulation of immature, malignant cells in the bone marrow. This block in differentiation is often caused by loss-of-function mutations in transcription factors that regulate genes important for the differentiation process. The transcription factor PU.1 is a key player in blood development, and evidence from PU.1 knockout mice indicates that PU.1 is absolutely required for the differentiation of myeloid-lineage cells and B lymphocytes. Reduced PU.1 levels, on the other hand, led to AML in mice, and its expression is significantly inhibited in human AML patients. Interestingly, untimely increased PU.1 expression is directly involved in the pathogenesis of red blood cell leukemias. 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 less well studied. Of note, we recently published that PU.1 binds to and inhibits the p53 tumor suppressor. Based on these findings, we will further analyze the oncogenic mechanisms by which PU.1 inhibits the p53 family of tumor suppressors. Moreover, we identified novel putative PU.1 target genes involved in proliferation and survival of hematopoietic 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 survival. In general, the proposed studies should help us to clarify the dual role of PU.1 as differentiation-inducing gene and as oncogene in myeloid cells via its interaction with the p53 tumor suppressor family as well as newly identified targets involved in cell survival.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
The actin-binding protein CORO1A is a novel PU.1 (SPI1)- and CEBPA-regulated gene with significantly lower expression in APL and CEBPA-mutated AML patients
Elena A. Federzoni, Magali Humbert, Peter J.M. Valk, Gerhard Behre, Elisabeth O. Leibundgut, Bruce E. Torbett, Martin F. Fey, Mario P. Tschan (2012), The actin-binding protein CORO1A is a novel PU.1 (SPI1)- and CEBPA-regulated gene with significantly lower expression in APL and CEBPA-mutated AML patients, in British Journal of Haematology, bjh.12170.
Transcriptional regulation of MIR29B by PU.1 (SPI1) and MYC during neutrophil differentiation of acute promyelocytic leukaemia cells.
Batliner Jasmin, Buehrer Emanuel, Federzoni Elena A, Jenal Mathias, Tobler Andreas, Torbett Bruce E, Fey Martin F, Tschan Mario P (2012), Transcriptional regulation of MIR29B by PU.1 (SPI1) and MYC during neutrophil differentiation of acute promyelocytic leukaemia cells., in British journal of haematology, 157(2), 270-4.
PU.1 is linking the glycolytic enzyme HK3 in neutrophil differentiation and survival of APL cells.
Federzoni Elena A, Valk Peter J M, Torbett Bruce E, Haferlach Torsten, Löwenberg Bob, Fey Martin F, Tschan Mario P, PU.1 is linking the glycolytic enzyme HK3 in neutrophil differentiation and survival of APL cells., in Blood.

Collaboration

Group / person Country
Types of collaboration
Department for Haematology and Oncology, University Hospital of Leipzig, Leipzig Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
annual AACR meeting 31.03.2012 Chicago, USA
53rd ASH Annual Meeting and Exposition 10.12.2011 San Diego, USA
ESH-EHA Scientific Workshop AML "Molecular" 14.10.2011 Mandelieu, France
Annual meeting of the Swiss Society of Hematology 11.05.2011 Lausanne, Switzerland


Awards

Title Year
DKF Travel Award 2011
DKF Travel Award 2011
ESH Scholarship 2011

Associated projects

Number Title Start Funding scheme
143739 PU.1-regulated apoptosis and autophagy pathways in neutrophil differentiation of normal and leukemic myeloid precursor cells 01.01.2013 Project funding (Div. I-III)
118276 Analyzing the oncogenic role of the hematopoietic transcription factor PU.1 01.10.2007 Project funding (Div. I-III)

Abstract

A hallmark of acute myeloid leukemia (AML) is an impairment of normal myeloid differentiation that leads to a clonal expansion of early immature myeloid progenitors. This block in differentiation is mostly caused by loss-of-function mutations in hematopoietic transcription factors that govern the orderly commitment of a cell to a particular hematopoietic lineage. The transcription factor RUNX1 (or AML1), for example, is involved in the translocation (8;21) that gives rise to the fusion protein AML1-ETO exerting a dominant inhibitory effect on wild-type functions of AML1. Similarly, the translocation t(15;17) causing a fusion of the retinoic acid receptor alpha (RARA) to the PML gene, found in acute promyelocytic leukemia (APL) patients, exerts a dominant negative effect on retinoic acid target genes. Both leukemic fusion proteins inhibit, among others, the transcriptional activator PU.1. In line, evidence from PU.1 knockout mice indicates that PU.1 is absolutely required for the differentiation of myeloid-lineage cells and B lymphocytes. Historically, there is a plethora of reports analyzing the role of PU.1 in myeloid and lymphoid differentiation, but its role in cellular proliferation and survival is only poorly studied. It has been shown that PU.1 is essential for self-renewal and proliferation of hematopoietic stem and progenitor cells. We now hypothesize that PU.1 in addition to its well-defined role in differentiation might impact on several cell growth pathways. We recently published that PU.1 reduces the transcriptional activity of the p53 tumor suppressor family and thus inhibits activation of genes important for cell cycle regulation and apoptosis. In addition, we identified several putative PU.1 transcriptional targets involved in cell proliferation/survival including the anti-apoptotic BCL2A1 and hexokinase III genes. As opposed to the differentiation of neutrophils and macrophages, differentiation of erythroid cells is dependent on PU.1 inactivation. High, untimely expression of PU.1 in pro-erythroblasts blocks differentiation and is associated with cell cycle disorder and increased proliferation. Preliminary data in leukemic PU.1 transgenic erythroblasts indicate that inhibiting PU.1 in these cells leads to apoptosis associated with upregulation of p53 family target genes. This would support our findings that PU.1 attenuates p53 family activity. In addition, upregulation of the above mentioned anti-apoptotic genes might support the erythroleukemic phenotype. Lastly, in the same analysis we found an upregulation of the pro-apoptotic kinase DAPK2, which is inhibited by PU.1 in our experiments.Based on our initial studies and published data I propose to study the proliferative and pro-survival characteristics of PU.1 in AML and erythroleukemia aiming atI. (a) analyzing the mechanism of how PU.1 inhibits activation of p53 family target genes, (b) studying the effects of the PU1/p53 interaction on PU.1 target genes, (c) testing how PU.1 levels influence the response of AML cells to cytotoxic drugs by inactivating the p53 family, and (d) analyzing the role of the novel, anti-apoptotic PU.1 targets BCL2A1 and if validated hexokinase III (HK3) in AML chemoresistance.II. (a) testing whether a release of PU.1 repression on p53 proteins is responsible for the cell death seen in leukemic erythroblasts, (b) characterizing the role of the novel anti-apoptotic PU.1 targets, BCL2A1 and HK3, in erythroleukemia cell survival, and (c) investigating the PU.1-DAPK2 link in erythroleukemia.These studies will enable us to further understand how PU.1 impacts on cellular proliferation and survival either via attenuating the p53 family pathway and/or via activation of anti-apoptotic or inactivation of pro-apoptotic genes in AML and erythroleukemia. Moreover, our findings may suggest improved chemotherapeutic interventions in APL by optimizing the sequence of differentiation- and cytotoxicity-inducing drugs.
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