Principal investigator

Prof. Dr. med. Stephan Stilgenbauer
Department of Internal Medicine III
University of Ulm
Albert-Einstein-Allee 23
89081 Ulm
Phone: 0731-500-45521
stephan.stilgenbauer(at)uniklinik-ulm.de

Curriculum Vitae

Project co-initiator and designated external collaborator
Prof. Dr. med. Karl Lenhard Rudolph
Institute of Molecular Medicine and
Max-Planck-Research Group for Stem Cell Aging
University of Ulm
Albert-Einstein-Allee 11
89081 Ulm
Phone: 0731-500-36100 / 0731-500-36102
lenhard.rudolph(at)uni-ulm.de

Summary

Telomere dysfunction has been suggested to have pathogenic and prognostic impact in chronic lymphocytic leukemia (CLL). In this project we will determine associations of telomere shortening and genomic instability with disease characteristics and outcome in samples from a clinical CLL trial. In addition, we will use mouse models of CLL and telomere dysfunction to experimentally address the relevant pathomechanisms of telomere dysfunction in CLL initiation and progression. Stable small interfering (si)RNA screens will be employed to determine the function of commonly deleted genes in the progression of CLL. These studies will delineate the role of telomere dysfunction in initiation, progression and treatment resistance of CLL.

B1

Telomere dysfunction in pathogenesis and clinical course of CLL

Publications

S. Stilgenbauer:

Jebaraj BM, Kienle D, Lechel A, Mertens D, Heuberger M, Ott G, Rosenwald A, Barth TF, Möller P, Zenz T, Döhner H, Stilgenbauer S. Telomere length in mantle cell lymphoma. Blood. 2013 Feb 14;121(7):1184-7. doi: 10.1182/blood-2012-08-452649. Epub 2012 Dec 14.1.

Bhattacharya N, Diener S, Idler IS, Barth TF, Rauen J, Habermann A, Zenz T, Möller P, Döhner H, Stilgenbauer S, Mertens D. Non malignant B-cells and chronic lymphocytic leukemia cells induce a prosurvival phenotype in CD14+ cells from the peripheral blood. Leukemia. 2011;25(4):722-6.

Zenz T, Mertens S, Küppers R, Döhner H, Stilgenbauer S. From pathogenesis to treatment of chronic lymphocytic leukemia. Nat Rev Cancer. 2010;10(1):37-50.

Roos G, Kröber A, Grabowski P, Kienle D, Bühler A, Döhner H, Rosenquist R, Stilgenbauer S. Short telomeres are associated with genetic complexity, high-risk genomic aberrations, and short survival in chronic lymphocytic leukemia. Blood. 2008;111(4):2246-2252.

Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910-6.

KL Rudolph:

Song Z, Wang J, Guachalla LM, Terszowskif G, Ju Z, Rudolph KL. Alterations of the systemic environment are the primary cause of impaired B- and T-lymphopoiesis in telomere dysfunctional mice. Blood. 2010;115:1481-9.

Begus-NahrmannY, Lechel A, Obenauf AC, NalapareddyK, Peit E, Hoffmann E, Schlaudraff F, Liss B, Schirmacher P, Kestler H, Danenberg E, BarkerN, Clevers H, Speicher MR, Rudolph KL. p53 deletion impairs clearance of chromosomal instable stem cells in aging telomere dysfunctional mice. Nat Genet. 2009,41:1138-43.

 

Jiang H, Schiffer E, Song Z, Wang J, Zürbig P, Thedieck K, Moes S, Bantel H, Saal N, Jantos J, Brecht M, Jenö P, Hall MN, Hager K, Manns MP, Hecker H, Ganser A, Döhner K, Bartke A, Meissner C, Mischak H, Ju Z, Rudolph KL. Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease. Proc Natl Acad Sci U S A. 2008;105(32):11299-304.

Ju Z, Jiang H, Jaworski M, Rathinam C, Gompf A, Klein C, Trumpp A, Rudolph KL.Telomere dysfunction induces environmental defects limiting hematopoietic stem cell function and engraftment. Nat Med. 2007;13(6):742-7.

Choudhury AR, Ju Z, Djojosubroto MW, Schienke A, Lechel A, Schaetzlein S, Jiang H, Stepczynska A, Wang C, Buer J, Lee HW, von Zglinicki T, Ganser A, Schirmacher P, Nakauchi H, Rudolph KL. Cdkn1a deletion improves stem cell function and life span of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet. 2007;39(1):99-105.

Schaetzlein S, Kodandaramireddy NR, Ju Z, Lechel A, Stepczynska A, Lilli DR, Clark AB, Rudolph C, Kuhnel F, Wei K, Schlegelberger B, Schirmacher P, Kunkel TA, Greenberg RA, Edelmann W, Rudolph KL. Exo1 deletion impairs DNA damage signaling and prolongs lifespan of telomere dysfunctional mice. Cell. 2007;130(5):863-77.

Ju Z, Jiang H, Jaworski M, Rathinam C, Gompf A, Klein C, Trumpp A, Rudolph KL. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat Med. 2007;13(6):742-7.