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Veterinärmedizinische Universität Wien

Jak-Stat signalling, Cdk6 and NK Cells

Veronika Sexl

Overview

My research group is dedicated to study signalling pathways in tumor cells with an emphasis on leukemia research. The aim is to understand how tumor cells rewire their signalling to maintain a transformed state. Only a precise understanding of the complex molecular networks driving leukemogenesis will allow us to interfere by developing novel therapeutics.

JAK2-STAT5 - a core cancer pathway for leukemogenesis

This field of research specialises on the role of Stats, Jaks and connected pathways in mouse leukaemia models. The lab addresses the role of Stat5 in Bcr/Abl- induced leukaemia and the role of MHC-class I antigens in immuno-surveillance of experimental leukaemias induced by the Abelson virus.

Janus kinases (Jaks) and signal transducers and activators of transcription (Stats) form a unique, fast track for signal transduction from cell surface receptors to target genes. Jak-Stat signalling contributes in many ways to the integrity of organisms and disturbance of this signalling avenue causes disease in mammalian organisms, including humans.

Publications

1. Warsch W, Grundschober E, Berger A, Gille L, Cerny-Reiterer S, Tigan AS, Hoelbl-Kovavic A, Valent P, Morriggl R, Sexl V.
STAT5 triggers BCR-ABL1 mutation by mediating ROS production in chronic myeloid leukaemia. Oncotarget. 2012 Dec;3(12):1669-1687

2. Warsch W, Walz C, Sexl V.
JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia. Blood. 2013 Sep 26;122(13):2167-2175. DOI: 10.1182/blood-2013-02-485573. Epub 2013 Aug 7.

3. Berger A, Hoelbl-Kovacic A, Bourgeais J, Hoefling L, Warsch W, Grundschober E, Uras I, Gouilleux F, Sexl V.
PAK-dependent STAT5 serine phosphorylation is required for BCR-ABL-induced leukemogenesis. Leukemia. 2014 Mar;28(3):629-41. DOI: 10.1038/leu.2013.351. Epub 2013 Nov 22.

4. Grundschober E, Hoelbl-Kovacic A, Bhagwat N, Kovacic B, Scheicher R, Eckelhart E, Kollmann K, Keller M, Grebien F, Wagner KU, Levine RL, Sexl V.
Acceleration of Bcr-Abl+ leukemia induced by deletion of JAK2. Leukemia. 2014 Sep;28(9):1918-22. DOI: 10.1038/leu.2014.152. Epub 2014 May 5.

5. Edlinger L, Berger-Becvar A, Menzl I, Hoermann G, Greiner G, Grundschober E, Bago-Horvath Z, Al-Zoughbi W, Hoefler G, Brostjan C, Gille L, Moriggl R, Spittler A, Sexl V, Hoelbl-Kovacic A.
Expansion of BCR/ABL1+ cells requires PAK2 but not PAK1. British Journal of Haematology. 2017 Jul 14. DOI: 10.1111/bjh.14833.

CDK6 - new functions for an old kinase

Known CDK6-mediated functions

Protein kinases represent one of the most popular target classes for the drug discovery. More than a dozen kinase inhibitors have been approved for clinical utility against cancer over the last decades and hundreds are undergoing numerous clinical trials. Among those, cyclin dependent kinase (CDK) 4/6 inhibitors received much attention in the past years.  The CDK4/6 inhibitor Palbociclib (IBRANCE by Pfizer) has received a breakthrough therapy designation by the Food and Drug Administration (FDA) in 2013 and has been approved in 2015 to treat breast cancer patients.

The two cell cycle enzymes CDK4 and CDK6 normally facilitate cell cycle progression to DNA synthesis. In certain cancers, CDK4 and CDK6 are abnormally activated, yet their deregulation is associated with different tumor types. In fact, in hematopoietic malignancies CDK6 is the predominant cell cycle kinase. CDK6 is overexpressed in lymphoid malignancies and has been defined as an essential effector of MLL-rearranged acute myeloid leukemia to maintain the undifferentiated immature state of progenitors.
However, at the mechanistic level, the pro-tumorigenic functions of CDK6 but not its functional homolog CDK4 go beyond cell cycle progression: the groundbreaking research from our group revealed that in lymphoid leukemia CDK6 but not CDK4 contributes to malignant transformation. CDK6 mediates deregulation of cell cycle progression and -unexpectedly- facilitates transcription of disease maintaining genes such as VEGF-A and p16INK4A. Of clinical relevance, leukemic stem cells depend on the transcriptional activity of CDK6 to inflict BCR/ABL driven neoplasm in mice.

Hence, our findings offer a novel valuable basis for drug discovery and emphasize the need to develop more sophisticated CDK6 inhibitors that also enable targeting the kinase-independent functions of CDK6 to obtain a more effective treatment response.

Publications

1. Bellutti F, Tigan AS, Nebenfuehr S, Dolezal M, Zojer M, Grausenburger R, Hartenberger S, Kollmann S, Doma E, Prchal-Murphy M, Uras IZ, Höllein A, Neuberg DS, Ebert BL, Ringler A, Mueller AC, Loizou JI, Hinds PW, Vogl C, Heller G, Kubicek S, Zuber J, Malumbres M, Farlik M, Villunger A, Kollmann K, Sexl V.
CDK6 antagonizes p53-induced responses during tumorigenesis.Cancer Discov. 2018 Jun 13. pii: CD-17-0912. DOI: 10.1158/2159-8290.CD-17-0912.

2. Kollmann K, Heller G, Schneckenleithner C, Warsch W, Scheicher R, Ott R, Schäfer M, Fajmann S, Schlederer M, Schiefer AI, Reichart U, Mayerhofer M, Hoeller C, Zoechbauer-Mueller S, Kerjaschki D, Bock C, Kenner L, Hoefler G, Freissmuth M, Green AR, Moriggl R, Busslinger M, Malumbres M, Sexl V.
A kinase-independent function of CDK6 links the cell cycle to tumor angiogenesis. Cancer Cell. 2013 Aug 12;24(2):167-81. DOI: 10.1016/j.ccr.2013.07.012.

3. Rodriguez-Diez E, Quereda V, Bellutti F, Prchal-Murphy M, Partida D, Eguren M, Gómez de Cedrón M, Dubus P, Canamero m, Martinez D, Sexl V, Malumbres M.
Cdk4 and Cdk6 cooperate in counteracting the INK4 family of inhibitors during murine leukemogenesis. Blood. 2014 Oct 9;124(15):2380-90. DOI: 10.1182/blood-2014-02-555292. Epub 2014 Aug 25.

4. Scheicher R, Hoelbl-Kovacic A, Bellutti F, Tigan AS, Prchal-Murphy M, Heller G, Schneckenleithner C, Salazar-Roa M, Zöchbauer-Müller S, Zuber J, Malumbres M, Kollmann K, Sexl V.
CDK6 as a key regulator of hematopoietic and leukemic stem cell activation. Blood. 2015 Jan 1;125(1):90-101. DOI: 10.1182/blood-2014-06-584417. Epub 2014 Oct 23.

5. Uras IZ, Walter GJ, Scheicher R, Bellutti F, Prchal-Murphy M, Tigan AS, Valent P, Heidel FH, Kubicek S, Scholl C, Fröhling S, Sexl V.
Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6. Blood. 2016 Jun 9;127(23):2890-902. DOI: 10.1182/blood-2015-11-683581. Epub 2016 Apr 20.

6. Uras IZ, Scheicher RM, Kollmann K, Glösmann M, Prchal-Murphy M, Tigan AS, Fux DA, Altamura S, Neves J, Muckenthaler MU, Bennett KL, Kubicek S, Hinds PW, von Lindern M, Sexl V.
Cdk6 contributes to cytoskeletal stability in erythroid cells. Haematologica. 2017 Jun;102(6):995-1005. DOI: 10.3324/haematol.2016.159947.Epub 2017 Mar 2.

NK cell attacking a tumor cell

NK-cells - silent killers on the move

Although the existence of tumor surveillance remained controversial for much of the past century there is now conclusive proof that the host immune system has an important role in the fight against cancer. This is also evident from the fact that in the year 2013 the Science Magazine chose cancer immunotherapy as breakthrough of the year.

Among the immune cells that have the ability to eliminate tumor cells are natural killer (NK) cells. NK cells are part of the innate immune system and play a pivotal role in the eradication of virally infected and transformed cells. NK cell development, proliferation and activity has to be tightly controlled, which is achieved by the absence or presence of distinct cytokines in bone marrow, spleen or at the site of inflammation.

Special attention is currently paid to NK cells in the fight against minimal residual disease (MRD). MRD consists of dormant tumor cells highly resistant to conventional chemotherapy that may survive for years in patients even after full clinical remission. In our current projects we try to understand the molecular machinery regulating NK cell activity to investigate how we could therapeutically arm NK cells to better combat malignant disease.

Publications

1. Eckelhart E, Warsch W, Zebedin E, Simma O, Stoiber D, Kolbe T, Rülicke T, Müller M, Casanova E, Sexl V.
A novel Ncr1-Cre mouse reveals the essential role of STAT5 for NK-cell survival and development. Blood. 2011 Feb 3;117(5):1565-73. DOI: 10.1182/blood-2010-06-291633. Epub 2010 Dec 2.

2. Putz EM, Gotthardt D, Hoermann G, Csiszar A, Wirth S, Berger A, Straka E, Rigler D, Wallner B, Jamieson AM, Pickl WF, Zebedin-Brandl EM, Müller M, Decker T, Sexl V.
CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance. Cell Rep. 2013 Aug 15;4(3):437-44. DOI: 10.1016/j.celrep.2013.07.012. Epub 2013 Aug 8.

3. Gotthardt D, Putz EM, Straka E, Kudweis P, Biaggio M, Poli V, Strobl B, Müller M, Sexl V.
Loss of STAT3 in murine NK cells enhances NK cell-dependent tumor surveillance. Blood. 2014 Oct 9; 124(15):2370-9. DOI: 10.1182/blood-2014-03-564450. Epub 2014 Sep 2.

4. Gotthardt D, Prchal-Murphy M, Seillet C, Glasner A, Mandelboim O, Carotta S, Sexl V, Putz EM.
NK cell development in bone marrow and liver: site matters. Genes Immun. 2014 Dec;15(8):584-7. DOI: 10.1038/gene.2014.55. Epub 2014 Oct 16.

5. Gotthardt D, Putz EM, Grundschober E, Prchal-Murphy M, Straka E, Kudweis P, Heller G, Bago-Horvath Z, Witalisz-Siepracka A, Cumaraswamy AA, Hunning PT, Strobl B, Müller M, Moriggl R, Stockmann C, Sexl V.
STAT5 is a key regulator in NK cells and acts as molecular switch from tumor surveillance to tumor promotion. Cancer Discovery. 2016 Feb 16; DOI: 10.1158/2159-8290.CD-15-0732.

6. Putz EM, Majoros A, Gotthardt D, Prchal-Murphy M, Zebedin-Brandl EM, Fux DA, Schlattl A, Schreiber RD, Carotta S, Müller M, Gerner C, Decker T, Sexl V.
Novel non-canonical role of STAT1 in Natural Killer cell cytotoxicity. Oncoimmunology. 2016 May 19;5(9):e1186314.

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