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Klinik für Innere Medizin IHämatologie, Onkologie und Stammzelltransplantation

Cancer Epigenetics

Molekularbild

Forschungsschwerpunkt

Der Schwerpunkt der AG liegt in der Erforschung der epigenetischen Pathomechanismen bei Leukämien, Präleukämien (Myelodysplastische Syndrome) und dem Lungenkarzinom.
Langfristiges Ziel ist eine Verbesserung der Prognose von Patienten mit diesen Erkrankungen über die Entwicklung epigenetisch basierter Therapieansätze und prädiktiver Biomarker.

Dipl. Biol. Gabriele Greve

Dr. Gabriele Greve

Postdoc

Telefon +49 (0) 761 270-71960

gabriele.greve@uniklinik-freiburg.de

Ruth Meier

Ruth Meier

Medizinische Doktorandin

ruth.meier@uniklinik-freiburg.de

Dr. Julia Stomper

Dr. Julia Stomper

Ärztin

julia.stomper@uniklinik-freiburg.de

Tzu-Ting Wei

Tzu-Ting Wei

PhD Student

tzu-ting.wei@uniklinik-freiburg.de

Anne Rubarth

Anne Rubarth

Masterstudentin

anne.rubarth@uniklinik-freiburg.de

Bettina Berberich

Bettina Berberich

Wissenschaftliche Hilfskraft

bettina.berberich@uniklinik-freiburg.de

Frederik Henes

Praktikant

frederik.henes@uniklinik-freiburg.de

Dana Roxanne Eble

Dana Roxanne Eble

Wissenschaftliche Hilfskraft | September bis Dezember 2018

  • Dr. Jörg Galle, Leipzig
  • Prof. Dr. Joop Jansen, Nijmegen, Niederlande
  • Prof. Dr. Ricky Johnstone, Melbourne
  • Prof. Peter A. Jones, Grand Rapids, MN, USA
  • Prof. H. Phillip Koeffler, Los Angeles, USA; Singapore
  • Prof. Dr. Frank Lyko, Heidelberg
  • Prof. Dr. Seishi Ogawa, Kyoto, Japan
  • Prof. Dr. Christoph Plass, Heidelberg

Ausgewählte präklinische und translationale Publikationen

  • Essig A, Duque-Afonso J, Schwemmers S, Pahl HL*, Lübbert M*. The AML1/ETO target gene LAT2 interferes with differentiation of normal hematopoietic precursor cells. Leuk Res. 38:340-5, 2014 (* contributed equally)  
  • Becker H, Yoshida K, Blagitko-Dorfs N, Claus R, Pantic M, Abdelkarim M, Niemöller C, Greil C, Hackanson B, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Döhner K, Schnittger S, Henneke P, Niemeyer CM, Flotho C, Pfeifer D, Ogawa S, Lübbert M. Tracing the development of acute myeloid leukemia in CBL-syndrome, Blood 123:1883-6, 2014  
  • Blagitko-Dorfs N, Jiang Y, Duque-Afonso J, Hiller J, Yalcin A, Greve G, Abdelkarim M, Hackanson B, Lübbert M. Epigenetic priming of AML blasts for all-trans retinoic acid-induced differentiation by the HDAC class-I selective inhibitor Entinostat. PLoS One Oct 8, 2013  
  • Solari L, Bauer T, Dicker F, Haferlach C, Grießhammer M, Schnittger S, Becker H*, Lübbert M*. A novel recurrent AML1-ETO fusion: tight in vivo association with BCR-ABL1. Leukemia 27:1397-400, 2013 (* contributed equally)  
  • Claus R, Pfeifer D, Almstedt M, Zucknick M, Hackanson B, Plass C, Lübbert M. Decitabine induces very early in vivo DNA methylation changes in blasts from patients with acute myeloid leukemia. Leuk Res. 37:190-6, 2013  
  • Hackanson B, Rimmele L, Benkißer M, Abdelkarim M, Fliegauf M, Jung M, Lübbert M. HDAC6 as a target for antileukemic drugs in acute myeloid leukemia. Leuk Res. 36(8):1055-62, 2012    
  • Müller-Schmah C, Solari L, Weis R, Pfeifer D, Scheibenbogen C, Trepel M, May AM, Engelhardt R, Lübbert M. Immune response as a possible mechanism of long-lasting disease control in spontaneous remission of MLL/AF9-positive acute myeloid leukemia. Ann. Hematol. 91:27-32, 2012
  • Duque-Afonso J, Berg T, Heidenreich O, Lübbert M.  The HDAC class I specific inhibitor Entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO. Oncogene  30:3062-72, 2011  
  • Duque-Afonso J, Solari L, Essig A, Berg T, Pahl HL, Lübbert M.  Regulation of the adaptor molecule LAT2, an in vivo target gene of AML1/ETO, during myeloid differentiation. Br. J. Haematol. 153:612-22, 2011   
  • Almstedt M, Blagitko-Dorfs N, Duque-Afonso J, Karbach J, Pfeifer D, Jäger E, Lübbert M. The DNA demethylating agent 5-aza-2'-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells. Leuk Res. 34:899-905, 2010  
  • Hackanson B, Abdelkarim M, Jansen JH, Lübbert M.  NHR4 domain mutations of ETO are probably very infrequent in AML1-ETO positive myeloid leukemia cells.  Leukemia  24(4):860-1, 2010
  • Chevalier N, Solari ML, Becker H, Pantic M, Gärtner F, Maul-Pavicic A, Hübner J, Wäsch R, Schmitt-Gräff A, Lübbert M. Robust in vivo differentiation of t(8;21)-positive acute myeloid leukemia blasts to neutrophilic granulocytes induced by treatment with dasatinib. Leukemia 24:1779-81, 2010
  • Haas PS, Roy NB, Gibbons RJ, Deville MA, Fisher C, Schwabe M, Bissé E, van Dorsselaer A, Higgs DR, Lübbert M. The role of X-inactivation in the gender bias of patients with acquired alpha-thalassaemia and myelodysplastic syndrome (ATMDS).  Br. J. Haematol. 144:538-45, 2009  
  • Flotho C, Claus R, Batz C, Schneider M, Sandrock I, Ihde S, Plass C, Niemeyer CM, Lübbert M. The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on gene expression in acute myeloid leukemia cells. Leukemia 23:1019-28, 2009
  • Berg T, Fliegauf M, Burger J, Staege SM, Liu S, Martinez N, Heidenreich O, Burdach S, Haferlach T, Werner MH, Lübbert M.  Transcriptional upregulation of p21/WAF/Cip1 in myeloid leukemic blasts expressing AML1-ETO.  Haematologica 93:1728-33, 2008  
  • Becker H, Pfeifer D, Duque-Afonso J, Nimer SD, Veelken H, Schwabe M, Lübbert M.  Two cell lines of t(8;21) acute myeloid leukemia with activating c-KIT exon 17 mutation: models for the “second hit” hypothesis. Leukemia 22:1792-4, 2008    
  • Berg T, Guo Y, Abdelkarim M, Fliegauf M, Lübbert M.  Regional demethylation and protein reexpression of p15/INK4b by 5-aza-2´-deoxcytidine is associated with growth inhibition in myeloid leukemia cells.  Leuk. Res. 31:497-506, 2007
  • Claus R, Fliegauf M, Stock M, Duque-Afonso J, Kolanczyk M, Lübbert M. Inhibitors of DNA methylation and histone deacetylation independently relieve AML1/ETO-mediated lysozyme repression J.  Leukoc. Biol. 80:1462-72, 2006    
  • Guo Y, Engelhardt M, Wider D, Abdelkarim M,  Lübbert M.  Effects of 5-aza-2´-deoxycytidine on proliferation, differentiation and p15/INK4b regulation of human hematopoietic progenitor cells. Leukemia, 20:115-21, 2006  
  • Schmelz K, Sattler N, Wagner M, Lübbert M, Dörken B, Tamm I. Induction of gene expression by 5-Aza-2'-deoxycytidine in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) but not epithelial cells by DNA-methylation-dependent and -independent mechanisms.  Leukemia 19:103-111, 2005  
  • Fliegauf M, Stock M, Berg T, Lübbert M. Williams-Beuren Syndrome Critical Region-5/Non-T Cell Activation Linker: a novel target gene of AML1/ETO. Oncogene 23:9070-81, 2004  
  • Daskalakis M, Nguyen TT, Nguyen C, Guldberg P, Köhler G, Wijermans P, Jones PA, Lübbert M. Demethylation of a hypermethylated p15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2'-deoxycytidine treatment.  Blood 100, 2957-2964, 2002   Nguyen C, Liang G, Nguyen TT, Tsao-Wei D, Groshen S, Lübbert M, Zhou JH, Benedict WF, Jones PA.  Susceptibility of nonpromoter CpG islands to de novo methylation in normal and neoplastic cells.  J. Nat. Cancer Inst.  93:1465-1472, 2001

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Ausgewählte klinische Publikationen

  • Döhner H, Lübbert M, Fiedler W, Fouillard L, Haaland A, Brandwein JM, Lepretre S, Reman O, Turlure P, Ottmann OG, Müller-Tidow C, Krämer A, Raffoux E, Döhner K, Schlenk RF, Voss F, Taube T, Fritsch H, Maertens J. Randomized, phase 2 trial comparing low-dose cytarabine with or without volasertib in AML patients not suitable for intensive induction therapy. Blood Jul 8, 2014
  • Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia, Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 369:111-21, 2013  
  • Lübbert M, Bertz H, Müller MJ, Finke J. When azanucleoside treatment can be curative: nonintensive bridging strategy before allografting in older patients with myelodysplastic syndrome/acute myeloid leukemia. J Clin Oncol. 31:822-3, 2013
  • Deschler B, Ihorst G, Platzbecker U, Germing U, März E, de Figuerido M, Fritzsche K, Haas P, Salih H, Giagounidis A, Selleslag D, Labar B, de Witte T, Wijermans P, Lübbert M. Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syn dromes and acute myeloid leukemia are highly predictive for outcome. Haematologica 98:208-16, 2013
  • Lübbert M, Rüter BH, Claus R, Schmoor C, Schmid M,  Germing U, Kuendgen A, Rethwisch V, Ganser A, Platzbecker U, Galm O, Brugger W, Heil G, Hackanson B, Deschler B, Döhner K, Hagemeijer A, Wijermans PW, Döhner H.  A multicenter phase II trial of continued Decitabine as first-line treatment of older AML patients judged unfit for induction chemotherapy. Haematologica 97(3):393-401, 2012
  • Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, Muus P, Te Boekhorst P, Sanz G, Del Cañizo C, Guerci-Bresler A, Nilsson L, Platzbecker U, Lübbert M, Quesnel B, Cazzola M, Ganser A, Bowen D, Schlegelberger B, Aul C, Knight R, Francis J, Fu T, Hellström-Lindberg E.  MDS-004 Lenalidomide del 5q Study Group. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood 118:3765-76, 2011
  • Lübbert M, Suciu S, Baila L, Rüter B, Platzbecker U, Giagounidis A, Selleslag D, Labar B, Germing U, Salih HR, Beeldens F, Muus P, Pflüger KH, Coens C, Hagemeijer A, Schaefer HE, Ganser A, Aul C, de Witte T, Wijermans PW. Low-dose decitabine vs. Best Supportive Care in elderly patients with intermediate- or high-risk MDS ineligible for intensive chemotherapy: final results of the randomized phase III study of the EORTC Leukemia Group and the German MDS Study Group.  J. Clin. Oncol.  29:2889-96, 2011  
  • Lübbert M, Bertz H, Wäsch R, Marks R, Rüter B, Claus R, Finke J.  Efficacy of a 3-day, low-dose treatment with 5-azacytidine followed by donor lymphocyte infusions in older patients with acute myeloid leukemia or chronic myelomonocytic leukemia relapsed after allografting.  Bone Marrow Transpl. 43, August 31, 2009
  • Lübbert M, Bertz H, Rüter B, Marks R, Claus R, Wäsch R, Finke J. Non-intensive treatment with low-dose 5-aza-2'-deoxycytidine (DAC) prior to allogeneic blood stem cell transplantation of older MDS/AML patients.  Bone Marrow Transpl. 43, April 13, 2009
  • Wijermans PW, Rüter B, Baer MR, Slack JL, Saba HI, Lübbert M.  Efficacy of decitabine in the treatment of patients with chronic myelomonocytic leukemia (CMML).  Leuk. Res. 32:587-91, 2008.
  • Haase D, Germing U, Schanz J, Pfeilstöcker M, Nösslinger T, Hildebrandt B, Kündgen A, Lübbert M, Kunzmann R, Giagounidis A, Aul C, Trümper L, Krieger O, Stauder R, Müller TH, Wimazal F, Valent C, Fonatsch C, Steidl C.  New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients.  Blood 110:4385-95, 2007
  • Rüter B, Wijermans P, Claus R, Kunzmann R, Lübbert M. Preferential cytogenetic response to continuous intravenous low-dose Decitabine (DAC) administration in myelodysplastic syndrome with chromosome 7 abnormalities.  Blood 110:1080-2, 2007
  • Rüter B, Wijermanns PW, Lübbert M. Superiority of prolonged low-dose azanucleoside administration? Results of 5-aza-2´deoxycytidine retreatement in high-risk myelodysplasia patients.  Cancer, 106:1744-50, 2006
  • Wijermans PW, Lübbert M, Verhoef G, Klimek V, Bosly A. An epigenetic approach to the treatment of advanced MDS; the experience with the DNA demethylating agent 5-aza-2'-deoxycytidine (decitabine) in 177 patients.  Ann. Hematol. 84 Suppl 13:9-17, 2005
  • Pitako JA, Haas P, van den Bosch J, Müller-Berndorf H, Kündgen A, Germing U, Wijermans PW, Lübbert M. Low-dose decitabine (DAC) in elderly MDS patients: quantification of hospitalization vs outpatient management and survial.  Ann. Hematol. 84 Suppl 13:125-31, 2005
  • van den Bosch, J., Lübbert, M., Verhoef, G., Wijermans, PW. The effects of 5-aza-2′-deoxycytidine (Decitabine) on the platelet count in patients with intermediate and high-risk myelodysplastic syndromes. Leuk Res 28:785-790, 2004
  • Lübbert M, Daskalakis M, Kunzmann R, Engelhardt M, Guo Y, Wijermans P. Nonclonal neutrophil responses after successful treatment of myelodysplasia with low-dose 5-aza-2´-deoxycytidine (Decitabine). Leuk Res 28:1267-71, 2004
  • Lübbert M, Wijermans P, Kunzmann R, Verhoef G, Bosly S Ravoet, C Andre, M Ferrant A.  Cytogenetic normalization in high-risk myelodysplastic syndrome following continued low-dose treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine (decitabine). Br. J. Haemat.114:349-357, 2001
  • Wijermans P, Lübbert M, Verhoef G, Bosly A, Ravoet C, Andre M Ferrant, A. Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients.   J. Clin. Oncol. 18:956-962, 2000

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Ausgewählte Übersichtsartikel und Buchkapitel

  • Navada SC, Steinmann J, Lübbert M, Silverman LR. Clinical development of demethylating agents in hematology. J Clin Invest. 124:40-6, 2014
  • Daskalakis M, Joeckel TE, Lübbert M, Kuendgen A. Treatment of Hematologic Malignancies with DNA Epigenetic Agents. In "Epigenetic Therapy of Cancer" (Editors: Lübbert M, Jones PA) Springer 2014, pp. 145-170.
  • 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. 68:5512-8, 2008
  • Kuendgen A, Lübbert M. Current status of epigenetic  treatment in myelodysplastic syndromes. Ann. Hematol. Apr 5, 2008
  • Lübbert M, Müller-Tidow C, Hofmann WK, Koeffler HP.  Advances in the treatment of acute myeloid leukemia: from chromosomal aberrations to biologically targeted therapy.  J. Cell. Biochem. 104:2059-70, 2008
  • Müller AM, Duque-Afonso J, Shizuru JA, Lübbert M. Complementing mutations in core binding factor leukemias: from mouse models to clinical applications. Oncogene 27:5759-73, 2008
  • Schwabe M, Lübbert M.  Epigenetic lesions in malignant melanoma.  Curr. Pharm. Biotechnol. 8:382-7, 2007.
  • Deschler B, de Witte T, Mertelsmann R, Lübbert M.  Decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches.  Haematologica 91:1513-22, 2006
  • Deschler B, Lübbert M.  Acute myeloid leukemia: epidemiology and etiology.  Cancer, 107:2099-107, 2006.
  • Digel W, Lübbert M.  DNA  methylation disturbances as novel therapeutic  target in lung cancer: preclinical and clinical results. Crit. Rev. Oncol. Hematol. 55:1-11, 2005
  • Claus R, Almstedt M, Lübbert M.  Epigenetic treatment of hematopoietic  malignancies: in vivo targets of demethylating agents. Semin. Oncol. 32: 511-20, 2005
  • Lübbert M.  Combined targeting of the epigenetic silence in leukemia: Cooperating activities of DNA methylation and histone deacetylation inhibitors. Leuk. Res. 29:727-8, 2005
  • Hackanson B, Guo Y, Lübbert M. The silence of the genes: epigenetic disturbances in haematopoietic malignancies. Expert Opin. Ther. Targets. 2005 Feb;9(1):45-61.

Epigenetic
Therapy of Cancer

Preclinical Models and
Treatment Approaches

Lübbert, Michael, Jones, Peter A.
(Eds.) 2014


Myelodysplastic Syndromes and
Acute Myeloid Leukemia:
A Biological and Therapeutic Continuum

Michael Lübbert and Steven D. Gore


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