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Klinik für Innere Medizin IHämatologie, Onkologie und Stammzelltransplantation

AG Dierks

The major goal of our research group is to identify novel stemness and kinase targets in hematologic malignancies and solid tumors, which can then be used to develop novel treatment strategies for these cancer entities. We have previously identified hedgehog signaling as essential for stem cell maintenance in chronic myeloid leukemia and lymphoid malignancies (Dierks et al Nature Medicine 2007, Cancer Cell 2008, Blood 2012) and found that hyperactivation of hedgehog signaling within the niche promotes leukemia formation in mice (JEM 2016). Furthermore, we identified SYK and PIM kinases as driving force for lymphoma cell growth and metastasis of solid tumors (Cancer Research 2009, 2010, MCT 2014). In addition, we have characterized novel oncogenes in hematologic malignancies in murine bone marrow transplantation models and in xenograft models (Cancer Research 2010, BCJ 2014). Our current focus is on pathways mediating the interaction of leukemic stem cells with the stem cell niche, the characterization of novel T-cell lymphoma oncogenes in vitro and in vivo and the validation of HH signaling as the first niche target preventing leukemic transformation of myeloproliferative diseases. In addition we are establishing a platform for research on anaplastic thyroid carcinomas including orthotopic xenograft mouse models, sequencing of anaplastic thyroid carcinoma patient samples and the establishment of transgenic mouse models resembling anaplastic thyroid cancers.

Hedgehog signaling in leukemic stem cells and the stem cell niche

Claudius Klein, Tony Müller, Sandra Kissel, Benjamin Rister

Novel therapeutic targets in CLL and T-cell lymphomas
(Hedgehog, PIM kinase, MAPK8, JQ1, BMPR4,...)

Sarah Decker, Shifaa Saleem

Kinases as targets in hematologic malignancies and solid tumors

SYK: Amelie Proske, Sudheer Gambeer, Larissa Link, Jevgeny Alexandrowsky

STK36 and others: Thomas Benkler, Andres Rettig

Postdocs

Dr. rer. nat. Claudius Klein

Dr. rer. nat. Claudius Klein    

claudius.klein@uniklinik-freiburg.de

Dr. rer. nat. Sarah Decker

Dr. rer. nat. Sarah Decker    

sarah.decker@uniklinik-freiburg.de

Dr. rer. nat. Tony Müller

Dr. rer. nat. Tony Müller    

tony.mueller@uniklinik-freiburg.de

Cell culture of primary CLL/MPN cells and AML blasts/ 3D-cell culture/Migration assays

Stem cell assays (in vitro and in vivo)
LTC-IC assays, Limiting dilution assays, stem cell competition assays

Facs and isolation of HSCs and niche cells
BM-endothelial cells, osteoblasts, CaR cells, MSCs

Bone marrow transplantation models in mice
(12 different AML models)

Xenograft models for CLL/AML/T-cell lymphoma patient samples into  NOG mice

Orthotopic xenografts for pancreatic cancer and ovarian cancer /In vivo metastasis models

Emmy Noether-Programm

  • Emmy-Noether program DFG

DFG - Deutsche Forschungsgemeinschaft

  • FOR2033 Nichem Forschergruppe
  • AML Forschergruppe

Deutsche Krebshilfe

  • CLL: HH und PIM in der CLL
  • T-Zell Lymphome: TZR und JAK/STAT signaling

  • Dierks C, Warmuth M, and Wu X. Biphenylcarboxamide derivates as hedgehog pathway modulators (published 18.12.2008), WO 2008/154259 A1 (International publication number).
  • Dierks C, and Warmuth M. Combination of Smo and Abl inhibitors in CML therapy. (published 26.02.2009), WO 2009/026075 A1.
  • Adrian F, Dierks C, Gray NS, Warmuth M. Combination of ATP-competitive BCR-ABL inhibitor and a non-ATP competitive BCR-ABL inhibitor (published 23.07.09), WO 2009/091476 A1.
  • Dierks C, and Warmuth M. Hedgehog pathway as a target in lymphomas and leukemias Patent number: P1257US00 / Submitted August 16,2007, Application number 60/956,295.

Publications (10 most important)

  1. Herrtwich L, Nanda I, Evangelou K, Nikolova T, Horn V, Erny D, Stefanowski J, Rogell L, Klein C, Gharun K, Follo M, Seidl M, Kremer B, Münke N, Senge J, Fliegauf M, Aschman T, Pfeif D, Sarrazin S, Sieweke M, Wagner D, Dierks C, Haaf T, Ness T, Zaiss M, Voll R, Deshmukh S, Prinz M, Goldmann T, Hölscher C, Hauser A, Lopez A, Grün D, Gorgoulis V, Diefenbach A, Henneke P, and Triantafyllopoulou A.
    DNA damage signaling instructs polyploid macrophage fate in granulomas
    Cell, 2016 Nov 17;167(5):1264-1280.e18. doi: 10.1016/j.cell.2016.09.054.   
  2. Klein C, Zwick A, Kissel S, Decker S, Benkler T, Pahl H, Illert AL, Oostendorp R, Duyster J,  Dierks C.
    Ptch2 loss drives myeloproliferation and MPN progression.
    J Exp Med. 2016 Feb 8;213(2):273-90
  3. Decker S, Finter J, Forde AJ, Kissel S, Schwaller J, Mack TS, Kuhn A, Gray N, Follo M, Jumaa H, Burger M, Zirlik K, Pfeifer D, Miduturu CV, Eibel H, Veelken H, Dierks C (2014)
    Dual role of PIM kinases in CLL, PIM1 regulates CXCR4 surface expression and  PIM 2/3 CLL cell survival.
    Mol Cancer Ther 2014, 13, 1231-1245.
  4. Sprissler C, Belenki D, Maurer H, Aumann K, Pfeifer D, Klein C, Müller TA, Hülsdünker J, Alexandrowski J, Brummer T, Jumaa H, Duyster J, Dierks C (2014)
    Depletion of STAT5 blocks TEL-SYK induced APMF-type leukemia with myelofibrosis and myelodysplasia in mice.  
    Blood Cancer Journal 2014, 22, e240.
  5. Decker S, Zirlik K, Djebatchie L, Hartmann D, Ihorst G, Schmitt-Graeff A, Herchenbach D, Jumaa H,   Warmuth M, Veelken H, Dierks C (2012) Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL.
    Blood 2012, 119, 997-1007.
  6. Zhang J, Adrián FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, Sim T, Powers J, Dierks C, Sun F, Guo GR, Ding Q, Okram B, Choi Y, Wojciechowski A, Deng X, Liu G, Fendrich G, Strauss A, Vajpai N, Grzesiek S, Tuntland T, Liu Y, Bursulaya B, Azam M, Manley PW, Engen JR, Daley GQ, Warmuth M, Gray NS (2010)
    Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors.
    Nature 2010, 463, 501-506.
  7. Dierks C, Adrian F, Ma H, Guo G, Zirlik K, Stegert M, Beigi R, Veelken H,  Warmuth M (2010)
     ITK-SYK induces T-cell lymphomas in mice mimicking human disease.
    Cancer Res. 2010, 73, 6193-6204.  
  8. Buchner M, Fuchs S, Prinz G, Pfeifer D, Bartholomé K, Chevalier N, Vallat L, Timmer J, Gribben JG, Jumaa H, Veelken H, Dierks C*, Zirlik K* (2009)
    Spleen Tyrosine Kinase (SYK) is Overexpressed and Represents a Potential Therapeutic Target in Chronic Lymphocytic Leukemia. *contributed equally
    Cancer Res. 2009, 69, 5424-5432.
  9. Dierks C, Beigi R, Stegert M, Zirlik K, Guo G, Schmitt-Graeff A, Veelken H, Warmuth M (2008)
    Hedgehog signaling is essential for expansion of Bcr-Abl positive leukemic stem cells.
    Cancer Cell 2008, 14, 238-249.
  10. Dierks C, Grbic J, Zirlik K, Beigi R, Englund NP, Veelken H, Engelhardt M, Mertelsmann R, Kelleher J, Schultz P, Warmuth M (2007)
    Essential role of stromally induced hedgehog signalling in B-cell malignancies.
    Nature Medicine 2007,13, 944-951.


Publications

2016

Klein C, Zwick A, Kissel S, Decker S, Benkler T, Pahl H, Oostendorp R, Duyster J,  Dierks C.
Ptch2 loss drives myeloproliferation and MPN progression.
J Exp Med. 2016 Feb 8;213(2):273-90 | (IF:12,9)

Herrtwich L, Nanda I, Evangelou K, Nikolova T, Horn V, Sagar, Erny D, Stefanowski J, Rogell L, Klein C, Gharun K, Follo M, Seidl M, Kremer B, Münke N, Senges J, Fliegauf M, Aschman T, Pfeifer D, Sarrazin S, Sieweke MH, Wagner D, Dierks C, Haaf T, Ness T, Zaiss MM, Voll RE, Deshmukh SD, Prinz M, Goldmann T, Hölscher C, Hauser AE, Lopez-Contreras AJ, Grün D, Gorgoulis V, Diefenbach A, Henneke P, Triantafyllopoulou A.
DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas.
Cell. 2016 Nov 17;167(5):1264-1280.e18. doi: 10.1016/j.cell.2016.09.054. | (IF; 32,2)

Benkisser-Petersen M, Buchner M, Dörffel A, Dühren-von-Minden M, Claus R, Kläsener K, Leberecht K, Burger M, Dierks C, Jumaa H, Malavasi F, Reth M, Veelken H, Duyster J, Zirlik K.
Spleen Tyrosine Kinase Is Involved in the CD38 Signal Transduction Pathway in Chronic Lymphocytic Leukemia.
PLoS One. 2016 Dec 30;11(12):e0169159. | (IF; 3,23)

2014

Bach MP, Hug E, Werner M, Holch J, Sprissler C, Pechloff K, Zirlik K, Zeiser R, Dierks C, Ruland J, Jumaa H.
Premature terminal differentiation protects from deregulated lymphocyte activation by ITK-Syk.
J Immunol. 2014 Feb 1;192(3):1024-33. | (IF:4,5)  

Decker S, Finter J, Forde AJ, Kissel S, Schwaller J, Mack TS, Kuhn A, Gray N, Follo M, Jumaa H, Burger M, Zirlik K, Pfeifer D, Miduturu CV, Eibel H, Veelken H, Dierks C.
Dual role of PIM kinases in CLL: PIM1 regulates CXCR4 surface expression and  PIM 2/3 CLL cell survival.
Mol Cancer Ther. 2014 May;13(5):1231-45. | (IF:5,7)

Sprissler C, Belenki D, Maurer H, Aumann K, Pfeifer D, Klein C, Müller TA, Hülsdünker J, Alexandrowski J, Brummer T, Jumaa H, Duyster J, Dierks C.
Depletion of STAT5 blocks TEL-SYK induced APMF-type leukemia with myelofibrosis and myelodysplasia in mice
Blood Cancer Journal, 2014 August; 22;4:e240. | (IF:3,5)

2013

Jutzi JS, Bogeska R, Nikoloski G, Schmid CA, Seeger TS, Stegelmann F, Schwemmers S, Gründer A, Peeken JC, Gothwal M, Wehrle J, Aumann K, Hamdi K, Dierks C, Kamar Wang W, Döhner K, Jansen JH, Pahl HL.
MPN patients harbor recurrent truncating mutations in transcription factor NF-E2.
J Exp Med. 2013 May 6;210(5):1003-19. |  (IF:12,9)

Brault L, Rovó A, Decker S, Dierks C, Tzankov A, Schwaller J.
CXCR4-SERINE339 regulates cellular adhesion, retention and mobilization, and is a marker for poor prognosis in acute myeloid leukemia.
Leukemia. 2013 Jul 2. doi: 10.1038/leu.2013.201. | (IF:10,5)

Yaktapour N, Ubelhart R, Schüler J, Aumann K, Dierks C, Burger M, Pfeifer D, Jumaa H, Veelken H, Brummer T, Zirlik K.
Insulin-like growth factor-1 receptor (IGF1R) as a novel target in chronic lymphocytic leukemia.
Blood. 2013 Aug 29;122(9):1621-33. | (IF:9.8)

2012

Decker S, Zirlik K, Djebatchie L, Hartmann D, Ihorst G, Schmitt-Graeff A, Herchenbach D, Jumaa H,   Warmuth M, Veelken H, Dierks C.
Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL.
Blood. 2012 Jan 26;119(4):997-1007. Epub 2011 Nov 30. | (IF:10,5)

2010

Zhang J, Adrián FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, Sim T, Powers J, Dierks C, Sun F, Guo GR, Ding Q, Okram B, Choi Y, Wojciechowski A, Deng X, Liu G, Fendrich G, Strauss A, Vajpai N, Grzesiek S, Tuntland T, Liu Y, Bursulaya B, Azam M, Manley PW, Engen JR, Daley GQ, Warmuth M, Gray NS.
Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors.
Nature. 2010 Jan 28;463(7280):501-6 | (IF:31,4)

Dierks C, Adrian F, Ma H, Guo G, Zirlik K, Stegert M, Beigi R, Veelken H, Warmuth M.
ITK-SYK induces T-cell lymphomas in mice mimicking human disease.
Cancer Res. 2010 Aug 1;70(15):6193-204 | (IF:7,5)

Buchner M, Baer C, Prinz G, Burger M, Zenz T, Stilgenbauer S, Dierks C, Jumaa H, Veelken H, Zirlik K.
Spleen Tyrosine Kinase Inhibition Prevents Chemokine- and Integrin-Mediated Stromal Protective Effects in Chronic Lymphocytic Leukemia.
Blood. 2010 Jun 3;115(22):4497-506 | (IF:10,5)

Brantner P, Stickel N, Prinz G, Burger M, Bär C, Dierks C, Pfeifer D, Ott A, Mertelsmann R, Gribben JG, Veelken H, Zirlik K.
The microenvironment differentially impairs passive and active immunotherapy in chronic lymphocytic leukaemia - CXCR4 antagonists as potential adjuvants for monoclonal antibodies.
British Journal of Haematology, 2010 151(2):167-78 |  (IF:4,5)

Hackanson B, Becker H, Berg T, Binder M, Dierks C, Duque-Afonso J, Lairmore MD, Schäfer HS, Schnitzler M, Zeiser R, Martens U, Mertelsmann R, Lübbert M.
XXIII International Association for Comparative Research on Leukemia and Related Diseases Symposium: from molecular pathogenesis to targeted therapy in leukemia and solid tumors.
Cancer Res. 2008 Jul 15;68(14):5512-8 | (IF:8,2)

2009

Buchner M, Fuchs S, Prinz G, Pfeifer D, Bartholomé K, Chevalier N, Vallat L, Timmer J, Gribben JG, Jumaa H, Veelken H, Dierks C*, Zirlik K*.
Spleen Tyrosine Kinase (SYK) is Overexpressed and Represents a Potential Therapeutic Target in Chronic Lymphocytic Leukemia. *contributed equally
Cancer Res. 2009 Jul 1;69(13):5424-32 | (IF:7,5)

Grundler R, Gasser C, Brault L, Bullock AN, Dechow T, Nawjin M, Berns A, Woetzel S, Pogacic V, Ehret S, Berridge G, Spoo A, Dierks C, Biondi A, Knapp S, Duyster J, Schwaller J.
PIM kinases in FLT3-ITD-mediated leukemia: unravelling of an essential function of PIM1 in early bone marrow homing and functional interaction with the SDF1α/CXCR4 axis.
J Exp Med. 2009 Aug 31;206(9):1957-70 | (IF:15,6)

2008

Dierks C, Beigi R, Stegert M, Zirlik K, Guo G, Schmitt-Graeff A, Veelken H, Warmuth M.
Hedgehog signaling is essential for expansion of Bcr-Abl positive leukemic stem cells.
Cancer Cell. 2008 Sep 9;14(3):238-49 | (IF:23,8)  

Dierks C. GDC-0449--targeting the hedgehog signaling pathway.
Recent Results Cancer Res. 2010;184:235-8. Review

2007

Dierks C, Grbic J, Zirlik K, Beigi R, Englund NP, Veelken H, Engelhardt M, Mertelsmann R, Kelleher J, Schultz P, Warmuth M.
Essential role of stromally induced hedgehog signalling in B-cell malignancies.
Nat. Med. 2007, 13: 944-951 | (IF:28,6)

2003

Schuster C (now Dierks C), Forster K, Dannhauser-Riedl S, Hallek M,  Warmuth M.
The effects of Bcr-Abl on C/EBP transcription-factor regulation and neutrophilic differentiation are reversed by the Abl kinase inhibitor imatinib mesylate.
Blood, 2003 Jan 15;101(2):655-63 | (IF:10,1)

AG Leitung
PD Dr. Christine Dierks

PD Dr. Christine Dierks | CV

christine.dierks@uniklinik-freiburg.de

Telefon+49-761 270 71812
Fax+49-761 270 71770

Adresse

Universitätsklinikum Freiburg
Klinik für Innere Medizin I
Hämatologie/Onkologie
Hugstetter Str. 55

D-79106 Freiburg