Source: http://jak-stat.at/research-groups/group-sexl/
Timestamp: 2019-04-24 03:52:32+00:00

Document:
We propose a novel mode by which STAT3 regulates the chromatin landscape in transformed haematopoietic cells in cooperation with the cell cycle regulator CDK6. We shall test this notion by means of BCR ABL+ and NPM-ALK+ tumours. If either STAT3 or CDK6 is absent, tumour formation is severely reduced. Our preliminary studies suggest a tight interaction of STAT3 and CDK6 on chromatin, which we intend to investigate further. Our investigations will include the STAT3 mutations that have been repeatedly found in human lymphoid malignancies. These clinically relevant STAT3 mutations will be studied in model cell lines and in vitro and in vivo in B and T lymphoid cells.
Our major goal is to test the ability of lymphocytes to propagate leukaemia, their epigenetic landscape and their interaction with CDK6. The work should reveal a novel layer of regulation of STAT3, mediated via its interaction with CDK6 and might open a novel therapeutic avenue to interfere with STAT3´s function.
Within the proposed project we aim to determine the stepwise cooperativity of STAT3 and TFs in gene induction and histone modification.
Hoelbl, A., Kovacic, B., Kerenyi, M.A., Simma, O., Warsch, W., Cui, Y., Beug, H., Hennighausen, L., Moriggl, R. and Sexl, V. (2006).
Clarifying the role of Stat5 in lymphoid development and Abelson-induced transformation.
Kovacic, B., Stoiber, D., Moriggl, R., Weisz, E., Ott, R. G., Kreibich, R., Levy, D.E., Beug, H., Freissmuth, M., and Sexl, V. (2006).
STAT1 acts as a tumor promoter for leukemia development.
Ott, R.G., Simma, O., Kollmann, K., Weisz, E., Zebedin, E.M., Schorpp-Kistner, M., Heller, G., Zochbauer, S., Wagner, E.F., Freissmuth, M. and Sexl, V. (2007).
Jun B is a gatekeeper for B-lymphoid leukemia.
Staber, P.B., Vesely, P., Haq, N., Ott, R.G., Funato, K., Bambach, I., Fuchs, C., Schauer, S., Linkesch, W., Hrzenjak, A., Dirks, W.G., Sexl, V., Bergler, H., Kadin, M.E., Sternberg, D.W., Kenner, L. and Hoefler, G. (2007).
The oncoprotein NPM-ALK of anaplastic large cell lymphoma induces JUNB transcription via ERK1/2 abd JunB translation via mTOR signaling.
Mayerhofer, M., Gleixner, K.V., Hoelbl, A., Florian, S., Hoermann, G., Aichberger, K.J., Bilban, M., Esterbauer, H., Krauth, M.T., Sperr, W.R., Longley, J.B., Kralovic, R., Moriggl, R., Zappulla, J., Liblau, R.S., Schwarzinger, I., Sexl, V., Sillaber, C. and Valent, P. (2008).
Unique effects of KIT D816V in BaF3 cells: induction of cluster formation, histamine synthesis, and early mast cell differentiation antigens.
Schuster, C., Müller, M., Freissmuth, M., Sexl, V. and Stoiber, D. (2008).
Commentary on H.Ide et al: “Tyk2 expression and its signaling enhances invasiveness of prostate cancer cells”.
Kornfeld, J.W., Grebien, F., Kerenyi, M.A., Friedbichler, K., Kovacic, B., Zankl, B., Hoelbl, A., Nivarti, H., Beug, H., Sexl, V., Müller, M., Kenner, L., Müllner, E.W., Gouilleux, F. and Moriggl, R. (2008).
The different functions of Stat5 and chromatin alteration through Stat5 proteins.
Mayerhofer, M., Gleixner, K.V., Mayerhofer, J., Hoermann, G., Jaeger, E., Aichberger, K.J., Ott, R.G., Greish, K., Nakamura, H., Derdak, S., Samorapoompichit, P., Pickl, W.F., Sexl, V., Esterbauer, H., Schwarzinger, I., Sillaber, C., Maeda, H. and Valent, P. (2008).
Targeting of heat shock protein 32 (Hsp 32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myleoid leukemia. A novel approach to overcome resistance against imatinib.
Zebedin, E., Simma, O., Schuster, C., Putz, E.M., Fajmann, S., Warsch, W., Eckelhart, E., Stoiber, D., Weisz, E., Schmid, J.A., Pickl, W.F., Baumgartner, C., Valent, P., Piekorz, R.P., Freissmuth, M. and Sexl, V. (2008).
Leukemic challenge unmasks a requirement for PI3Kdelta in NK cell-mediated tumor surveillance.
Pilz, A., Kratky, W., Stockinger, S., Simma, O., Kalinke, U., Lingnau, K., von Gabain, A., Stoiber, D., Sexl, V., Kolbe, T., Rulicke, T., Müller, M. and Decker, T. (2009).
Dendritic cells require STAT-1 phosphorylated at its transactivating domain for the induction of peptide-specific CTL.
Simma, O., Zebedin, E., Neugebauer, N., Schellack, C., Pilz, A., Chang-Rodriguez, S., Lingnau, K., Weisz, E., Putz, E.M., Pickl, W.F., Felzmann, T., Müller, M., Decker, T., Sexl, V. and Stoiber, D. (2009).
Identification of an indispensable role for tyrosine kinase 2 in CTL-mediated tumor surveillance.
Ecker, A., Simma, O., Hoelbl, A., Kenner, L., Beug, H., Moriggl, R. and Sexl, V. (2009).
The dark and the bright side of Stat3: proto-oncogene and tumor-suppressor.
Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia.
Beer-Hammer, S., Zebedin, E., von Holleben, M., Alferink, J., Reis, B., Dresing, P., Degrandi, D., Scheu, S., Hirsch, E., Sexl, V., Pfeffer, K., Nurnberg, B., and Piekorz, R.P. (2010).
The catalytic PI3K isoforms F28110gamma and F28110delta contribute to B cell development and maintenance, transformation, and proliferation.
Eckelhart, E., Warsch, W., Zebedin, E., Simma, O., Stoiber, D., Kolbe, T., Rulicke, T., Mueller, M., Casanova, E., and Sexl, V. (2011).
A novel Ncr1-Cre mouse reveals the essential role of STAT5 for NK cell survival and development.
Kornfeld, J.W., Isaacs, A., Vitart, V., Pospisilik, J.A., Meitinger, T., Gyllensten, U., Wilson, J.F., Rudan, I., Campbell, H., Penninger, J.M., Sexl, V., Moriggl, R., van Duijn, C., Pramstaller, P.P., and Hicks, A.A. (2011).
Mueller, K.M., Kornfeld, J.W., Friedbichler, K., Blaas, L., Egger, G., Esterbauer, H., Hasselblatt, P., Schlederer, M., Haindl, S., Wagner, K.U., Engblom, D., Haemmerle, G., Kratky, D., Sexl, V., Kenner, L., Kozlov, A.V., Terracciano, L., Zechner, R., Schuetz, G., Casanova, E., Pospisilik, J.A., Heim, M.H., and Moriggl, R. (2011).
Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice.
Schneckenleithner, C., Bago-Horvath, Z., Dolznig, H., Neugebauer, N., Kollmann, K., Kolbe, T., Decker, T., Kerjaschki, D., Wagner, K.-U., Müller, M., Stoiber, D., and Sexl, V. (2011).
Putting the brakes on mammary tumorigenesis: Loss of STAT1 predisposes to intraepithelial neoplasias.
The cooperating mutation or "second hit" determines the immunological visibility towards MYC-induced murine lymphomas.
Warsch, W., Kollmann, K., Eckelhart, E., Fajmann, S., Cerny-Reiterer, S., Holbl, A., Gleixner, K.V., Dworzak, M., Mayerhofer, M., Hoermann, G., Herrmann, H., Sillaber, C., Egger, G., Valent, P., Moriggl, R., and Sexl, V. (2011).
High STAT5 levels mediate imatinib resistance and indicate disease progression in chronic myeloid leukemia.
Friedbichler, K., Hoelbl, A., Li, G., Bunting, K.D., Sexl, V., Gouilleux, F., and Moriggl, R. (2011).
Serine phosphorylation of the Stat5a C-terminus is a driving force for transformation.
Strobl, B., Stoiber, D., Sexl, V., and Müller, M. (2011).
Tyrosine kinase 2 (Tyk2) in cytokine signalling and host immunity.
Kollmann, K., Heller, G., Ott, R.G., Scheicher, R., Zebedin-Brandl, E., Schneckenleithner, C., Simma, O., Warsch, W., Eckelhart, E., Hoelbl, A., Bilban, M., Zochbauer-Muller, S., Malumbres, M., and Sexl, V. (2011).
C-JUN promotes BCR-ABL induced lymphoid leukemia by inhibiting methylation of the 5' region of Cdk6.
PI3Kδ Is Essential for Tumor Clearance Mediated by Cytotoxic T Lymphocytes.
Warsch, W., Grundschober, E., Berger, A., Gille, L., Cerny-Reiterer, S., Tigan, A.-S., Hoelbl-Kovacic, A., Valent, P., Moriggl, R., and Sexl, V. (2012).
STAT5 triggers BCR-ABL1 mutation by mediating ROS production in chronic myeloid leukaemia.
Kernbauer, E., Maier, V., Stoiber, D., Strobl, B., Schneckenleithner, C., Sexl, V., Reichart, U., Kalinke, U., Reizis, B., Jamieson, A., Müller, M., and Decker, T. (2012).
Conditional Stat1 ablation reveals the importance of interferon signaling for immunity to Listeria monocytogenes infection.
Diverging fates of cells of origin in acute and chronic leukaemia.
Conditional IFNAR1 ablation reveals distinct requirements of Type I IFN signaling for NK cell maturation and tumor surveillance.
Putz, E.M., Zebedin, E., and Sexl, V. (2012).
STAT Transcription Factors: Controlling All Aspects of NK Cell Biology.
Kollmann, K., Heller, G., Schneckenleitner, C., Warsch, W., Scheicher, R., Ott, R.G., Schäfer, M., Fajmann, S., Schlederer, M., Schiefer, A.-I., Reichart, U., Mayerhofer, M., Hoeller, C., Zöchbauer-Müller, S., Kerjaschki, D., Bock, C., LKenner, L., Hoefler, G., Freissmuth, M., Green, A.R., Moriggl, R., Busslinger, M., Malumbres, M., and Sexl, V. (2013).
Köprülü, A.D., Kastner, R., Wienerroither, S., Lassnig, C., Putz, E.-M., Majer, O., Reutterer, B., Sexl, V., Kuchler, K., Müller, M., Decker, T., and Ellmeier, W. (2013).
The tyrosine kinase Btk regulates the macrophage response to Listeria monocytogenes infection.
Putz, E.M., Gotthardt, D., Hoermann, G., Csiszar, A., Wirth, S., Berger, A., Straka, E., Rigler, D., Wallner, B., Jamieson, A.M., Pickl, W.F., Zebedin-Brandl, E.M., Müller, M., Decker, T., and Sexl, V. (2013).
Hannesdottir, L., Tymoszuk, P., Parajuli, N., Wasmer, M.H., Philipp, S., Daschil, N., Datta, S., Koller, J.B., Tripp, C.H., Stoitzner, P., Muller-Holzner, E., Wiegers, G.J., Sexl, V., Villunger, A., and Doppler, W. (2013).
ETV6/RUNX1 Induces Reactive Oxygen Species and Drives the Accumulation of DNA Damage in B Cells.
Richter, K., Perriard, G., Behrendt, R., Schwendener, R.A., Sexl, V., Dunn, R., Kamanaka, M., Flavell, R.A., Roers, A., and Oxenius, A. (2013).
Macrophage and T cell produced IL-10 promotes vrial chronicity.
Warsch, W., Grundschober, E., and Sexl, V. (2013).
Adding a new facet to STAT5 in CML: Multitasking for leukemic cells.
Warsch, W., Walz, C., and Sexl, V. (2013).
JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia.
Koromilas, A.E., and Sexl, V. (2013).
The tumor suppressor function of STAT1 in breast cancer.
Berger, A., Sexl, V., Valent, P., and Moriggl, R. (2014).
Inhibition of STAT5: A therapeutic option in BCR-ABL1-driven leukemia.
Gotthardt, D., Putz, E.M., Straka, E., Kudweis, P., Biaggio, M., Poli, V., Strobl, B., Müller, M., and Sexl, V. (2014).
Loss of STAT3 in murine NK cells enhances NK cell-dependent tumor surveillance.
Kovacic, B., Hoelbl-Kovacic, A., Fischhuber, K.M., Leitner, N.R., Gotthardt, D., Casanova, E., Sexl, V., and Müller, M. (2014).
Lactotransferrin-Cre reporter mice trace neutrophils, monocytes/macrophages and distinct subtypes of dendritic cells.
Gotthardt, D., Prchal-Murphy, M., Seillet, C., Glasner, A., Mandelboim, O., Carotta, S., Sexl, V., and Putz, E.M. (2014).
NK cell development in bone marrow and liver: site matters.
Grundschober, E., Hoelbl-Kovacic, A., Bhagwat, N., Kovacic, B., Scheicher, R., Eckelhart, E., Kollmann, K., Keller, M., Grebien, F., Wagner, K.U., Levine, R.L., and Sexl, V. (2014).
Acceleration of Bcr-Abl leukemia induced by deletion of JAK2.
Putz, E.M., Hoelzl, M.A., Baeck, J., Bago-Horvath, Z., Schuster, C., Reichholf, B., Kern, D., Aberger, F., Sexl, V., and Hoelbl-Kovacic, A. (2014).
Loss of STAT3 in Lymphoma Relaxes NK Cell-Mediated Tumor Surveillance.
Klose, C.S., Flach, M., Mohle, L., Rogell, L., Hoyler, T., Ebert, K., Fabiunke, C., Pfeifer, D., Sexl, V., Fonseca-Pereira, D., Domingues, R.G., Veiga-Fernandes, H., Arnold, S.J., Busslinger, M., Dunay, I.R., Tanriver, Y., and Diefenbach, A. (2014).
Differentiation of Type 1 ILCs from a Common Progenitor to All Helper-like Innate Lymphoid Cell Lineages.
Prchal-Murphy, M., Witalisz-Siepracka, A., Bednarik, K.T., Putz, E.M., Gotthardt, D., Meissl, K., Sexl, V., Müller, M., and Strobl, B. (2015).
In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity.
Schneckenleithner, C., Hoelbl-Kovacic, A., and Sexl, V. (2015).
Modeling BCR/ABL-Driven Malignancies in the Mouse.
Bottos, A., Gotthardt, D., Gill, J.W., Gattelli, A., Frei, A., Tzankov, A., Sexl, V., Wodnar-Filipowicz, A., and Hynes, N.E. (2016).
Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models.
Gotthardt, D., Putz, E.M., Grundschober, E., Prchal-Murphy, M., Straka, E., Kudweis, P., Heller, G., Bago-Horvath, Z., Witalisz-Siepracka, A., Cumaraswamy, A.A., Gunning, P.T., Strobl, B., Muller, M., Moriggl, R., Stockmann, C., and Sexl, V. (2016).
STAT5 is a key regulator in NK cells and acts as molecular switch from tumor surveillance to tumor promotion.
Klose, R., Krzywinska, E., Castells, M., Gotthardt, D., Putz, E.M., Kantari-Mimoun, C., Chikdene, N., Meinecke, A.K., Schrodter, K., Helfrich, I., Fandrey, J., Sexl, V., and Stockmann, C. (2016).
Targeting VEGF-A in myeloid cells enhances natural killer cell responses to chemotherapy and ameliorates cachexia.
Majoros, A., Platanitis, E., Szappanos, D., Cheoan, H.J., Vogl, C., Shukla, P., Stark, G.R., Sexl, V., Schreiber, R.D., Schindler, C., Müller, M., and Decker, T. (2016).
Response to interferons and antibacterial innate immunity in absence of tyrosine-phosphorylated STAT1.
Putz, E.M., Majoros, A., Gotthart, D., Prchal-Murphy, M., Zebedin-Brandl, E., Fux, D.A., Schlattl, A., Schreiber, R.D., Carotta, S., Müller, M., Gerner, C., Decker, T., and Sexl, V. (2016).
Novel non-­canonical role of STAT1 in Natural Killer cell cytotoxicity.
Freund, P., Kerenyi, M.A., Hager, M., Wagner, T., Wingelhofer, B., Pham, H.T., Elabd, M., Han, X., Valent, P., Gouilleux, F., Sexl, V., Kramer, O.H., Groner, B., and Moriggl, R. (2017).
Linke, M., Pham, H.T., Katholnig, K., Schnoller, T., Miller, A., Demel, F., Schutz, B., Rosner, M., Kovacic, B., Sukhbaatar, N., Niederreiter, B., Bluml, S., Kuess, P., Sexl, V., Muller, M., Mikula, M., Weckwerth, W., Haschemi, A., Susani, M., Hengstschlager, M., Gambello, M.J., and Weichhart, T. (2017).
Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression.
Maurer, B., Farlik, M., and Sexl, V. (2017).
It is a differentiation game: STAT5 in a new role.
Glasner, A., Levi, A., Enk, J., Isaacson, B., Viukov, S., Orlanski, S., Scope, A., Neuman, T., Enk, C.D., Hanna, J.H., Sexl, V., Jonjic, S., Seliger, B., Zitvogel, L., and Mandelboim, O. (2018).
NKp46 Receptor-Mediated Interferon-gamma Production by Natural Killer Cells Increases Fibronectin 1 to Alter Tumor Architecture and Control Metastasis.
Pham, H.T.T., Maurer, B., Prchal-Murphy, M., Grausenburger, R., Grundschober, E., Javaheri, T., Nivarthi, H., Boersma, A., Kolbe, T., Elabd, M., Halbritter, F., Pencik, J., Kazemi, Z., Grebien, F., Hengstschlager, M., Kenner, L., Kubicek, S., Farlik, M., Bock, C., Valent, P., Muller, M., Rulicke, T., Sexl, V., and Moriggl, R. (2018).
Porpaczy, E., Tripolt, S., Hoelbl-Kovacic, A., Gisslinger, B., Bago-Horvath, Z., Casanova-Hevia, E., Clappier, E., Decker, T., Fajmann, S., Fux, D. A., Greiner, G., Gueltekin, S., Heller, G., Herkner, H., Hoermann, G., Kiladjian, J. J., Kolbe, T., Kornauth, C., Krauth, M. T., Kralovics, R., Muellauer, L., Mueller, M., Prchal-Murphy, M., Putz, E. M., Raffoux, E., Schiefer, A. I., Schmetterer, K., Schneckenleithner, C., Simonitsch-Klupp, I., Skrabs, C., Sperr, W. R., Staber, P. B., Strobl, B., Valent, P., Jaeger, U., Gisslinger, H. and Sexl, V.
Szappanos, D., Tschismarov, R., Perlot, T., Westermayer, S., Fischer, K., Platanitis, E., Kallinger, F., Novatchkova, M., Lassnig, C., Müller, M., Sexl, V., Bennett, K.L., Foong-Sobis, M., Penninger, J. and Decker, T.
Gawish, R., Bulat, T., Biaggio, M., Lassnig, C., Bago-Horvath, Z., Macho-Maschler, S., Poelzl, A., Simonovic, N., Prchal-Murphy, M., Rom, R., Amenitsch, L., Ferrarese, L., Kornhoff, J., Lederer, T., Svinka, J., Eferl, R., Bosmann, M., Kalinke, U., Stoiber, D., Sexl, V., Krmpotic, A., Jonjic, S., Muller, M. and Strobl, B.
Kollmann, S., Grundschober, E., Maurer, B., Warsch, W., Grausenburger, R., Edlinger, L., Huuhtanen, J., Lagger, S., Hennighausen, L., Valent, P., Decker, T., Strobl, B., Mueller, M., Mustjoki, S., Hoelbl-Kovacic, A. and Sexl, V.
Simonovic, N., Witalisz-Siepracka, A., Meissl, K., Lassnig, C., Reichart, U., Kolbe, T., Farlik, M., Bock, C., Sexl, V., Müller, M. and Strobl, B.
Witalisz-Siepracka, A., Klein, K., Ptinz, D., Leidenfrost, N., Schabbauer, G., Dohnal, A. and Sexl, V.

References: V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V.

 V.