Merkel research group at the Department of Pathology

Research

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Research Focus

Despite the identical genetic information in each of our cells, they vary greatly in function and appearance. The reason is the different use of this information in the respective cells. Incorrect use of the information can lead to serious diseases, including cancer.

The first level of gene regulation are the transcription factors. They bind DNA in the vicinity of their target genes and can influence their expression positively or negatively. However, there are also regulatory regions on the DNA that are not located near the target genes but nevertheless influence their expression, so-called "enhancers". The activity and architecture of the individual enhancer regions changes dynamically depending on cell type or differentiation status. Another level of regulation is performed by non-coding RNA molecules which are able to regulate gene transcription and protein expression. In this context we are studying microRNAs which are small non-coding RNA molecules that alter gene expression of their target genes and can be used as stable biomarkers or therapeutic targets.

We have explored the role of non-coding RNAs in chronic lymphocytic leukemia and anaplastic large cell lymphoma (Musilova et al. Blood 2018, Hoareau-Aveilla et al. Front. Biosci. 2015, Merkel et al. J. Pathol. 2015, Merkel et al. PNAS 2010) and elucidated modes of action of cancer-related transcription factors and tyrosine kinases (Liang et al. Nat. Com. 2021, Kornauth Cancer Discov. 2021, Schleussner/Merkel et al. Leukemia 2018, Prutsch et al. Leukemia 2019).

Main Objectives

The main interest of our group is to study the mechanisms that lead to lymphoma development in B and T-cell lymphomas. In this context we are looking at transcription factors and non-coding RNAs that are key for changing a healthy hematopoietic cell into a cancer cell. Factors we have studied include the JAK/STAT family of proteins, the p53 tumor suppressor and the AP-1 family of transcription factors. We have extensively monitored protein and non-coding RNA downstream targets of these factors.

In addition, we are interested in the role of thyroid hormone in prostate cancer and its interaction with androgen signaling. Goal of this project is to monitor whether the thyroid hormone in the case of androgen resistance can substitute for androgen signaling. This would open up a novel therapeutic window for androgen resistant prostate cancer.

Content Research

We use cancer cell lines and diverse cancer mouse models. We also use primary patient tissue to which we have particularly good access as an institute for pathology. Techniques used are RNA-seq, Ago2 immunoprecipitation, H3K27ac ChIP-seq, ATAC-seq. In order to identify new therapeutics, we also perform substance screens and chemical derivatization of lead compounds.

Projects

Non Coding-RNAs in Lymphoma

Lately, we have focused our interest on T-cell lymphoma, in particular Anaplastic Large Cell Lymphoma (ALCL) where we described deregulated non-coding RNAs in this disease and their functional implications. Interestingly, the patients with or without the NPM-ALK translocation over-express the oncogenic miR-17-92 cluster or the oncogenic miR-155, respectively, suggesting different mechanisms of oncogenesis.

BATF3 as Super Enhancer driven Transcription Factor in ALCL

We study the highly ALCL-specific transcription factor BATF3. Using genome wide H3K27ac ChIP-seq analysis in ALCL cell lines but also in primary patient tumor cells we have found that BATF3, STAT1, STAT3 and MCL1 genes reside in super- enhancer regions. BATF3 regulates the transcription of all three subunits of the trimeric IL-2 receptor and the IL-2 receptor, which can be used as a target structure for an armed antibody. In murine engraftment experiment we could show that this drug could stop tumor growth after one bolus injection.

TYK2 as tumor driver and immune-modulator in ALCL

Anaplastic Lymphoma Cells release high amounts of IL-10. The IL-10 receptor is expressed by ALCL cells and results in the activation of the tyrosine kinase TYK2. Therefore, we deleted TYK2 in a T-cell specific manner in the CD4-NPM-ALK mouse model and found a three-fold, longer overall survival, suggesting TYK2 as a strong NPM-ALK independent tumor driver in ALCL. However, TYK2 knockout has been shown to lead to higher susceptibility to pathogens and certain cancer types. Therefore, we currently study the potentially antagonistic effects on anti-cancer immunity when using small molecule which lead to systemic TYK2 inhibition.

Molecular Degrader Drugs for IRF4

We are now developing together with an organic chemist, small molecules that target the transcription factors identified by the super-enhancer screening mentioned above including IRF4 and IKZF1, with the goal to have new tailored drugs that have less side effects than the aggressive poly-chemotherapy that is currently used in these patients.

Staff

Assoc.-Prof. Priv.-Doz. Dr. Dipl.-Ing. Olaf MERKEL

Tel.: +43 (0)1 40400-68730
Fax: +43 (0)1 40400-51930
E-Mail: olaf.merkel@meduniwien.ac.at

» ORCID

Publications

Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematologic Cancers and Identifies Exceptional Responders.
Kornauth C, Pemovska T, Vladimer, Merkel O, et al. Staber PB.
Cancer Discov. 2022 Feb;12(2):372-387. PMID: 34635570, IF:39,4
Super-enhancer-based identification of a BATF3/IL-2R−module reveals vulnerabilities in anaplastic large cell lymphomaLiang H-C, Costanza M, Prutsch N, Zimmerman M, Gurnhofer E1, Montes-Mojarro I, Abraham BJ, Prokoph N, Stoiber S, Tangermann S, Lobello C, Oppelt J, Anagnostopoulos J, Hielscher T, Shahid Pervez S, Klapper W, Zammarchi F, Silva D-A, Garcia KC, Baker D, Janz M, Nikolai Schleussner, Fend F, Pospíšilová S, Wallwitz J, Stoiber D, Simonitsch-Klupp I, Cerroni L, Pileri S, Leval L, Sibon D, Fataccioli V, Gaulard P, Assaf C, Knörr F, Damm-Welk C, Woessmann W, Turner SD, Look AT, Mathas S, Kenner L, Merkel O
Nature Communications. 2021 Sep 22;12(1):5577. PMID: 34552066, IF: 14,9
STAT3 and TP53 mutations associate with poor prognosis in anaplastic large cell lymphoma.
Lobello C, Tichy B, Bystry V, Radova L, Filip D, Mraz M, Montes-Mojarro IA, Prokoph N, Larose H, Liang HC, Sharma GG, Mologni L, Belada D, Kamaradova K, Fend F, Gambacorti-Passerini C, Merkel O, Turner SD, Janikova A, Pospisilova S.
Leukemia. 2021 May;35(5):1500-1505. PMID: 33247178, IF: 11,5
Thyroid and androgen receptor signaling are antagonized by μ-Crystallin in prostate cancer.
Aksoy O, Pencik J, Hartenbach M, Moazzami AA, Schlederer M, Balber T, Varady A, Philippe C, Baltzer PA, Mazumder B, Whitchurch JB, Roberts CJ, Haitel A, Herac M, Susani M, Mitterhauser M, Marculescu R, Stangl-Kremser J, Hassler MR, Kramer G, Shariat SF, Turner SD, Tichy B, Oppelt J, Pospisilova S, Hartenbach S, Tangermann S, Egger G, Neubauer HA, Moriggl R, Culig Z, Greiner G, Hoermann G, Hacker M, Heery DM, Merkel O, Kenner L.
Int J Cancer. 2021 Feb 1;148(3):731-747. PMID: 33034050, IF: 7,4
IL10RA modulates crizotinib sensitivity in NPM1-ALK+ anaplastic large cell lymphoma.
Prokoph N, Probst NA, Lee LC, Monahan JM, Matthews JD, Liang HC, Bahnsen K, Montes-Mojarro IA, Karaca-Atabay E, Sharma GG, Malik V, Larose H, Forde SD, Ducray SP, Lobello C, Wang Q, Luan SL, Pospíšilová Š, Gambacorti-Passerini C, Burke GAA, Pervez S, Attarbaschi A, Janíková A, Pacquement H, Landman-Parker J, Lambilliotte A, Schleiermacher G, Klapper W, Jauch R, Woessmann W, Vassal G, Kenner L, Merkel O, Mologni L, Chiarle R, Brugières L, Geoerger B, Barbieri I, Turner SD.
Blood. 2020 Oct 1;136(14):1657-1669. PMID: 32573700, IF: 22,1
Whole Exome Sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target.
Larose H, Prokoph N, Matthews JD, Schlederer M, Högler S, Alsulami AF, Ducray SP, Nuglozeh E, Fazaludeen FMS, Elmouna A, Ceccon M, Mologni L, Gambacorti-Passerini C, Hoefler G, Lobello C, Pospisilova S, Janikova A, Woessmann W, Damm-Welk C, Zimmermann M, Federova A, Malone A, Smith O, Wasik M, Inghirami G, Lamant L, Blundell TL, Klapper W, Merkel O, Burke AGA, Mian S, Ashankyty I, Kenner L, Turner SD. Haematologica. 2021 Jun 1;106(6):1693-1704. PMID: 32327503, IF: 9,9
The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status.
Trigg RM, Lee LC, Prokoph N, Jahangiri L, Reynolds CP, Amos Burke GA, Probst NA, Han M, Matthews JD, Lim HK, Manners E, Martinez S, Pastor J, Blanco-Aparicio C, Merkel O, de Los Fayos Alonso IG, Kodajova P, Tangermann S, Högler S, Luo J, Kenner L, Turner SD.
Nature Communications. 2019 Nov 28;10(1):5428. PMID: 31780656, IF: 14,9
High activation of STAT5A drives peripheral T-cell lymphoma and leukemia.
Maurer B, Nivarthi H, Wingelhofer B, Pham HTT, Schlederer M, Suske T, Grausenburger R, Schiefer AI, Prchal-Murphy M, Chen D, Winkler S, Merkel O, Kornauth C, Hofbauer M, Hochgatterer B, Hoermann G, Hoelbl-Kovacic A, Prochazkova J, Lobello C, Cumaraswamy AA, Latzka J, Kitzwögerer M, Chott A, Janikova A, Pospíšilova Š, Loizou JI, Kubicek S, Valent P, Kolbe T, Grebien F, Kenner L, Gunning PT, Kralovics R, Herling M, Müller M, Rülicke T, Sexl V, Moriggl R.
Haematologica. 2020 Jan 31;105(2):435-447. PMID: 31123029, IF: 9,9
Hepatic growth hormone - JAK2 - STAT5 signalling: Metabolic function, non-alcoholic fatty liver disease and hepatocellular carcinoma progression.
Kaltenecker D, Themanns M, Mueller KM, Spirk K, Suske T, Merkel O, Kenner L, Luís A, Kozlov A, Haybaeck J, Müller M, Han X, Moriggl R.
Cytokine. 2019 Dec;124:154569. PMID: 30389231 Review, IF: 3,3
miR-150 downregulation contributes to the high-grade transformation of follicular lymphoma by upregulating FOXP1 levels.
Musilova K, Devan J, Cerna K, Seda V, Pavlasova G, Sharma S, Oppelt J, Pytlik R, Prochazka V, Prouzova Z, Trbusek M, Zlamalikova L, Liskova K, Kruzova L, Jarosova M, Mareckova A, Kornauth C, Simonitsch-Klupp I, Schiefer AI, Merkel O, Mocikova H, Burda P, Machova Polakova K, Kren L, Mayer J, Zent CS, Trneny M, Evans AG, Janikova A, Mraz M.
Blood. 2018 Sep 13. DOI: 10.1182/blood-2018-06-855502. PMID: 30213873, IF: 22,1
Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma.
Prutsch N, Gurnhofer E, Suske T, Liang HC, Schlederer M, Roos S, Wu LC, Simonitsch-Klupp I, Alvarez-Hernandez A, Kornauth C, Leone DA, Svinka J, Eferl R, Limberger T, Aufinger A, Shirsath N, Wolf P, Hielscher T, Aberger F, Schmoellerl J, Stoiber D, Strobl B, Jäger U, Staber PB, Grebien F, Moriggl R, Müller M, Inghirami GG, Sanda T, Look AT, Turner SD, Kenner L, Merkel O.
Leukemia. 2018 Aug 21. DOI: 10.1038/s41375-018-0239-1. PMID: 30131584, IF: 11,5
The Role of Activator Protein-1 (AP-1) Family Members in CD30-Positive Lymphomas.
Garces de Los Fayos Alonso I, Liang HC, Turner SD, Lagger S, Kenner L, Merkel O.
Cancers (Basel). 2018 Mar 28;10(4) DOI: 10.3390/cancers10040093. PMID: 29597249, IF: 6,6
BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma.
Merkel, O., Schleussner, N., Costanza, M., Liang, H.-C., Hummel, F., Romagnani, C., Durek, P., Anagnostopoulos, I., Hummel, M., Jöhrens, K., et al., Mathas S.
Leukemia. 2018 Sep;32(9):1994-2007. PMID: 29588546, IF: 11,5
Image-based ex-vivo drug screening for patients with aggressive haematological malignancies: interim results from a single-arm, open-label, pilot study.
Snijder B, Vladimer GI, Krall N, Miura K, Schmolke AS, Kornauth C, Lopez de la Fuente O, Choi HS, van der Kouwe E, Gültekin S, Kazianka L, Bigenzahn JW, Hoermann G, Prutsch N, Merkel O, et al., Superti-Furga G.
Lancet Haematol. 2017 Dec;4(12):e595-e606. PMID: 29153976, IF: 18,9
First-in-human response of BCL-2 inhibitor venetoclax in T-cell prolymphocytic leukemia. Boidol B, Kornauth C, van der Kouwe E, Prutsch N, Kazianka L, Gültekin S, Hoermann G, Mayerhoefer ME, Hopfinger G, Hauswirth A, Panny M, Aretin MB, Hilgarth B, Sperr WR, Valent P, Simonitsch-Klupp I, Moriggl R, Merkel O, Kenner L, Jäger U, Kubicek S, Staber PB.
Blood. 2017 Dec 7;130(23):2499-2503. PMID: 28972014, IF: 22.1
The effects of migratory flight on the hematologic parameters in northern bald ibises
Stanclova G, Schwendenwein I, Merkel O, Kenner L, Dittami J, Fritz J, Scope A.
J Zoo Wildl Med. 2017 Dec;48(4):1154-1164. doi: 10.1638/2016-0258.1.
When the guardian sleeps: Reactivation of the p53 pathway in cancer.
Merkel, O., Taylor, N., Prutsch, N., Staber, P.B., Moriggl, R., Turner, S.D., and Kenner, L.,
Mutation Research, 2017. 773: p. 1-13, PMID: 28927521, IF: 2.1
Insights into the Pathogenesis of Anaplastic Large-Cell Lymphoma through Genome-wide DNA Methylation Profiling.
Hassler MR, Pulverer W, Lakshminarasimhan R, Redl E, Hacker J, Garland GD, Merkel O, Schiefer AI, Simonitsch-Klupp I, Kenner L, Weisenberger DJ, Weinhaeusel A, Turner SD, Egger G.
Cell Rep. 2016 Oct 4;17(2):596-608. doi: 10.1016/j.celrep.2016.09.018.
PMID: 27705804 Free PMC article. PMID: 27705804, IF: 9.4
JAK-STAT signaling in cancer: From cytokines to non-coding genome.
Pencik J, Pham HT, Schmoellerl J, Javaheri T, Schlederer M, Culig Z, Merkel O, Moriggl R, Grebien F, Kenner L.
Cytokine. 2016 Nov;87:26-36. doi: 10.1016/j.cyto.2016.06.017. Epub 2016 Jun 24.
PMID: 27349799 Free PMC article. Review. IF: 3,3
Breaking a paradigm: IL-6/STAT3 signaling suppresses metastatic prostate cancer upon ARF expression. Culig Z, Pencik J, Merkel O, Kenner L.
Mol Cell Oncol. 2016 Apr 4;3(2):e1090048. doi: 10.1080/23723556.2015.1090048. eCollection 2016 Mar.
PMID: 27308625 Free PMC article.
Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress.
Malcolm TI, Villarese P, Fairbairn CJ, Lamant L, Trinquand A, Hook CE, Burke GA, Brugières L, Hughes K, Payet D, Merkel O, Schiefer AI, Ashankyty I, Mian S, Wasik M, Turner M, Kenner L, Asnafi V, Macintyre E, Turner SD.
Nat. Commun. 2016 Jan 12;7:10087. doi: 10.1038/ncomms10087.
PMID: 26753883 Free PMC article. IF: 14,9
Interleukin-6 receptor alpha blockade improves skin lesions in a murine model of systemic lupus erythematosus.
Birner P, Heider S, Petzelbauer P, Wolf P, Kornauth C, Kuroll M, Merkel O, Steiner G, Kishimoto T, Rose-John S, Soleiman A, Moriggl R, Kenner L. Interleukin-6 receptor alpha blockade improves skin lesions in a murine model of systemic lupus erythematosus.
Exp Dermatol. 2016 Apr;25(4):305-10. doi: 10.1111/exd.12934. Epub 2016 Feb 13.
PMID: 26739431 Free PMC article. IF: 4,0