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PU.1-regulated apoptosis and autophagy pathways in neutrophil differentiation of normal and leukemic myeloid precursor cells

English title PU.1-regulated autophagy and apoptosis pathways in neutrophil differentiation of normal and leukemic myeloid precursor cells
Applicant Tschan Mario P.
Number 143739
Funding scheme Project funding (Div. I-III)
Research institution Department for BioMedical Research Forschungsgruppe Radio-Onkologie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Experimental Cancer Research
Start/End 01.01.2013 - 30.06.2016
Approved amount 390'000.00
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All Disciplines (3)

Discipline
Experimental Cancer Research
Immunology, Immunopathology
Cellular Biology, Cytology

Keywords (4)

Autophagy; Apoptosis; Acute Myeloid Leukemia; PU.1

Lay Summary (German)

Lead
Analyse PU.1-regulierter Apoptose und Autophagie in der normalen und leukämischen Differenzierung von myeloischen Vorläuferzellen
Lay summary

Die akute myeloische Leukämie (AML) ist eine äusserst heterogene Krankheit, welche sich generell durch die Ansammlung unreifer Blutzellen auszeichnet. Die Heterogenität der AML ergibt sich aus der Tatsache, dass die leukämischen Blastzellen verschiedener AML Subtypen einen Differenzierungsstopp in unterschiedlichen Entwicklungsstufen normaler Vorläuferzellen reflektieren. Dieser Differenzierungsstopp basiert häufig auf der Inaktivierung spezieller Proteine, den Transkriptionsfaktoren, welche die Transkription von Genen kontrollieren. Ein essentieller Transkriptionsfaktor in der myeloischen Differenzierung ist PU.1. Die Inaktivierung von PU.1 in Mäusen führt zu einer fatalen Störung der myeloischen Zelldifferenzierung. Reduzierte PU.1 Expression reicht für die Entstehung von AML in Mäusen aus und die PU.1 Expression ist in AML Patienten signifikant reduziert. Meine und andere Forschungsgruppen konnten kürzlich zeigen, dass PU.1 eine neue Funktion in der direkten Regulierung von apoptotischen oder anti-apoptotischen Genen hat. Es wurde z.B. gezeigt, dass PU.1 das apoptotische Gen TRAIL reguliert. Wir identifizierten das anti-apoptotische Gen BCL2A1 und das glykolytische Gen Hexokinase 3 als neue PU.1 Zielgene mit einer Funktion im Überleben von neutrophilen Zellen. Erste Daten unserer Gruppe deuten daraufhin, dass PU.1 auch mehrere Gene des Autophagie Signalweges reguliert. Autophagie ist ein Degradationsprozess in der Zelle, welcher vor allem dem Abbau von Proteinaggregaten und defekten Organellen dient. Werden Zellen gestresst, z.B. durch den Entzug von Nährstoffen aber auch durch Chemotherapie, erlaubt die Autophagie den Zellen das Überleben. Andererseits, ist die Autophagie auch essentiell für die myeloische Differenzierung. Die Funktion von PU.1 in der terminalen myeloischen Differenzierung wurde bereits extensiv untersucht. Andererseits gibt es zur wahrscheinlichen Rolle von PU.1 im Zellüberleben und in der Apoptose von neutrophilen Zellen nur sehr wenige Studien. Wir werden deshalb weiter untersuchen, wie PU.1 das Überleben und den Zelltod von normalen und leukämischen Zellen reguliert, indem wir untersuchen ob PU.1 direkt Autophagie und Apoptose Gene reguliert. Ein besseres Verständnis dieser Prozesse wird der Etablierung neuer Ansätze für die Differenzierungs- als auch Chemotherapie von AML dienen. Zusätzlich werden die vorgeschlagenen Experimente neue Einblicke in die Zelltodmechanismen von neutrophilen Zellen geben.

Direct link to Lay Summary Last update: 24.01.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Human DMTF1β antagonizes DMTF1α regulation of the p14(ARF) tumor suppressor and promotes cellular proliferation.
Tschan Mario P, Federzoni Elena A, Haimovici Aladin, Britschgi Christian, Moser Bettina A, Jin Jing, Reddy Venkateshwar A, Sheeter Dennis A, Fischer Kimberlee M, Sun Peiqing, Torbett Bruce E (2015), Human DMTF1β antagonizes DMTF1α regulation of the p14(ARF) tumor suppressor and promotes cellular proliferation., in Biochimica et biophysica acta, 1849(9), 1198-1208.
Linking the SUMO protease SENP5 to neutrophil differentiation of AML cells.
Federzoni Elena A, Gloor Severin, Jin Jing, Shan-Krauer Deborah, Fey Martin F, Torbett Bruce E, Tschan Mario P (2015), Linking the SUMO protease SENP5 to neutrophil differentiation of AML cells., in Leukemia research reports, 4(1), 32-5.
Thiazolides promote apoptosis in colorectal tumor cells via MAP kinase-induced Bim and Puma activation.
Brockmann A, Bluwstein A, Kögel A, May S, Marx A, Tschan M P, Brunner T (2015), Thiazolides promote apoptosis in colorectal tumor cells via MAP kinase-induced Bim and Puma activation., in Cell death & disease, 6, 1778-1778.
CEBPA-dependent HK3 and KLF5 expression in primary AML and during AML differentiation.
Federzoni EA, Humbert M, Torbett BE, Behre G, Fey MF, Tschan MP (2014), CEBPA-dependent HK3 and KLF5 expression in primary AML and during AML differentiation., in Scientific Reports, 4261.
Induction of the autophagy-associated gene MAP1S via PU.1 supports APL differentiation.
Haimovici Aladin, Brigger Daniel, Torbett Bruce E, Fey Martin F, Tschan Mario P (2014), Induction of the autophagy-associated gene MAP1S via PU.1 supports APL differentiation., in Leukemia research, 38(9), 1041-7.
Investigation of IL-23 (p19, p40) and IL-23R identifies nuclear expression of IL-23 p19 as a favorable prognostic factor in colorectal cancer: a retrospective multicenter study of 675 patients.
Helbling Melina, Lukesch Anne, Haimovici Aladin, Karamitopoulou Eva, Berger Martin D, Hädrich Marion, Mallaev Makhmud, Schnüriger Beat, Koelzer Viktor H, Dawson Heather, Borner Markus, Langer Rupert, Rosenberg Robert, Nitsche Ulrich, Inderbitzin Daniel, Lugli Alessandro, Tschan Mario, Zlobec Inti (2014), Investigation of IL-23 (p19, p40) and IL-23R identifies nuclear expression of IL-23 p19 as a favorable prognostic factor in colorectal cancer: a retrospective multicenter study of 675 patients., in Oncotarget, 5(13), 4671-82.
p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells
Trocoli A., Bensadoun P., Richard E., Labrunie G., Merhi F., Schlaefli A. M., Brigger D., Souquere S., Pierron G., Pasquet J-M, Soubeyran P., Reiffers J., Segal-Bendirdjian E., Tschan M. P., Djavaheri-Mergny M. (2014), p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells, in CELL DEATH AND DIFFERENTIATION, 21(12), 1852-1861.
Pro-survival role of p62 during granulocytic differentiation of acute myeloid leukemia cells.
Ségal-Bendirdjian E (2014), Pro-survival role of p62 during granulocytic differentiation of acute myeloid leukemia cells., in Molecular & Cellular Oncology, e970066-1.
WIPI-dependent autophagy during neutrophil differentiation of NB4 acute promyelocytic leukemia cells.
Brigger D, Proikas-Cezanne T, Tschan M P (2014), WIPI-dependent autophagy during neutrophil differentiation of NB4 acute promyelocytic leukemia cells., in Cell death & disease, 5, 1315-1315.
The granulocyte orphan receptor CEACAM4 is able to trigger phagocytosis of bacteria.
Delgado TJ, Adrian J, Kopp K, Scholz P, Tschan MP, Kuespert K, Hauck CR, The granulocyte orphan receptor CEACAM4 is able to trigger phagocytosis of bacteria., in J Leukoc Biol.

Collaboration

Group / person Country
Types of collaboration
Bruce E. Torbett, The Scripps Research Institute, San Diego, CA United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Peter J.M. Valk, Erasmus University Medical Center, Rotterdam, the Netherlands Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Thomas Kaufmann, Institute of Pharmacology, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Benefizkonzert zu Gunsten der Krebsforschung, Fribourg, 2015 German-speaking Switzerland 2015
Talks/events/exhibitions Benefizkonzert zu Gunsten der Krebsforschung, Fribourg, 2014 German-speaking Switzerland 2014
Talks/events/exhibitions Benefizkonzert zu Gunsten der Krebsforschung, Fribourg, 2013 German-speaking Switzerland 2013

Awards

Title Year
Scholarship, European School of Hematology, AML workshop 2015
Travel grant award, AACR 2015

Associated projects

Number Title Start Funding scheme
157702 An apparatus for the real-time analysis of cellular metabolism 01.12.2014 R'EQUIP
173219 Identification and analysis of PU.1 cell death pathways to improve leukemia therapy 01.05.2017 Project funding (Div. I-III)
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)
129702 Functional analysis of the Death-associated protein kinase 2 (DAPK2) signalling pathway in acute myeloid leukaemias 01.04.2010 Project funding (Div. I-III)
173219 Identification and analysis of PU.1 cell death pathways to improve leukemia therapy 01.05.2017 Project funding (Div. I-III)

Abstract

PU.1-regulated apoptosis and autophagy pathways in neutrophil differentiation of normal and leukemic myeloid precursor cells1. Summary of the research planAcute myeloid leukemia (AML) is characterized by the accumulation of myeloid precursor cells that are blocked in their differentiation and show increased cell survival. A subgroup of AML patients, acute promyelocytic leukemia (APL) patients, is successfully treated with a combination of differentiation therapy using pharmacological doses of all-trans retinoic acid (ATRA) and chemotherapy. ATRA treatment resolves the differentiation block in APL cells via the proteasomal degradation of PML-RARA, the oncogenic fusion protein found in APL. Recently, two studies identified a function for autophagy in PML-RARA degradation induced by ATRA. Autophagy is a proteolytic self-degradation process characterized by the formation of double-membraned vesicles, autophagosomes, which engulf cytoplasmic contents. The autophagosomes then fuse with lysosomes allowing the degradation of its contents. Interestingly, inhibiting the autophagy machinery by knocking down autophagy-related genes (ATGs) also attenuates neutrophil differentiation of non-APL cells. An important PML-RARA-repressed gene is the myeloid master regulator PU.1. In normal hematopoiesis, studies in PU.1 null mice revealed that PU.1 is absolutely required for the development of several myeloid lineages as well as B lymphocytes. In these lineages PU.1 regulates the expression of many genes required for terminally differentiated cells to function. Importantly, PU.1 is not only repressed in APL but generally in AML. For example, direct repression of PU.1 transcription was seen by AML-ETO in AML with the translocation t(8;21) or by FLT-3 mutations. Thus, PU.1 repression is a common feature of most AML samples. The overall importance of PU.1 in myelopoiesis is further reflected by the fact that re-expression of PU.1 not only in APL but also in other AML subtypes can restore differentiation of the leukemic blasts. On the other hand, we and others described a new role for PU.1 in cell survival and apoptosis of neutrophils and other hematopoietic cells by directly regulating, depending on the cellular background, anti- or pro-apoptotic genes. For example, PU.1 regulates the pro-apoptotic gene TRAIL in cell death responses of myeloma cells. We showed that the Bcl2 family member BCL2A1 and the glycolytic enzyme hexokinase 3 (HK3) are novel PU.1 transcriptional targets that are involved in neutrophil cell survival. In summary, molecular pathways of normal myeloid cell differentiation, as well as the mechanisms by which oncogenes disrupt this process, remain poorly understood. Focusing on the myeloid master regulator PU.1 and its novel role in cell death and survival, I propose to address the following specific aims: I. PU.1 and apoptosis. I propose, (a) to analyze PU.1-mediated cell death mechanism in normal and leukemic myeloid cells, (b) to validate and characterize novel PU.1 transcriptional targets associated with cell death (CORO1A, c-FLIP, DAPK2) in myeloid cell survival, and (c) to further characterize the function of the novel PU.1 target hexokinase 3 in cell survival and metabolism of neutrophil cells. II. PU.1 and autophagy. I propose, (a) to investigate if PU.1 contributes to myeloid autophagy and (b) to characterize novel PU.1 transcriptional targets associated with autophagy (WIPI1, MAP1S) in myeloid differentiation and cell death responses.The proposed studies will shed further light on the mechanisms on how PU.1 impacts on cell survival and cell death of normal and leukemic myeloid cells via directly activating genes involved in apoptosis and autophagy. Understanding these processes will help to improve differentiation as well as cytotoxic therapies in the treatment of AML and will contribute to a better understanding of neutrophil cell death.
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