Bone marrow cells, so-called hematopoietic stem cells, form mature blood cells. If these cells lose this ability, the entire haematopoiesis is disrupted. The consequences are different disease pattern. Our research group investigates the role of genetic changes in hematopoietic stem cells and thus to the development of haematological neoplasia. Our scientific focus is to elucidate the mechanisms of genetic instability in myeloid neoplasia as well as underlying germline variants leading to those neoplasia. As possible causes for the development of complex karyotypes, we could describe excessive telomere shortening, altered DNA repair and TP53 variants (Feuerstein et al., Int J Mol Sci, 2018; Behrens et al., Genes Chromosomes Cancer 2019).
Our lab is accredited for cytogenetic and molecular diagnostics and we provide information on stratification relevant genetic markers for many (inter-)national study groups in the field of haematological neoplasia, e.g. chromosomal signature as detected by karyotyping, by fluorescence in situ hybridization (FISH), fusion genes as detected by RNA sequencing or mutational signatures as detected by next generation sequencing (NGS).
- Dr. rer. nat. Yvonne Behrens, Post-Doc
- Dr. rer. nat. Ilona Glowacka, Post-Doc
- Randa Bawadi, PhD-Student
- Andrea Schienke, VMTA
- Friederike Lutterloh, FWJ
Translational Research for Persons with Abnormal DNA Damage Response (ADDRess; BMBF 01GM1909A): Role of clonal evolution in the development of haematological neoplasia
Cancer predisposition syndromes (CPS) are genetic conditions associated with an increased cancer risk. CPSs are especially relevant for children and adolescents with cancer. We would like to learn more about the cancer risks in individuals affected by a CPS and about the biology underlying cancer development in these patients.
MyPred - MyPred - Optimizing care for young individuals with syndromes predisposing to myeloid malignancies (BMBF)
MyPred aims to identify recurrent changes in various predisposition syndromes, .Since somatic changes are to be identified that are characteristic for the malignant transformation of all predisposition syndromes, therapeutic approaches would be applicable for many patients (Göhring et al., Blood, 2010). Investigation of translocations and resulting fusion by targeted RNA sequencing could become an additional tool for assessing whether a patient has an acute risk of degeneration and thus complements mutation analysis and classic cytogenetics. The Panel-based RNA sequencing targets 1385 cancer genes and detects fusions between genes targeted by the panel but also fusions of targeted genes with non-target genes. The aim of the project is to detect genetic marker and fusion genes to help to assess the risk of transformation and thus, be relevant for prognosis and therapy.
Influence of telomere erosion on genetic instability
Telomeres cap and protect chromosome ends from degradation and fusion, and are therefore essential for maintaining chromosome stability and genomic integrity. Due to the end-replication problem there is a continuous telomere loss of 50 to 150 bp/cell cycle and thus throughout lifetime. The aim of this project is to better understand the role of telomere erosion and DNA double strand breaks in the development of haematological neoplasia (Göhring et al., Leukemia 2012; Behrens et al., Genes Chromosomes Cancer 2019). For telomere erosion we have established different methods for telomere lengths measurement which is used in daily routine accredited diagnostic (Behrens et al., Genes Chromosomes Cancer. 2017).
Selection of Publications
- Behrens YL, Thomay K, Hagedorn M, Ebersold J, Schmidt G, Lentes J, Davenport C, Schlegelberger B, Gohring G. Jumping translocations: Short telomeres or pathogenic TP53 variants as underlying mechanism in acute myeloid leukemia and myelodysplastic syndrome? Genes Chromosomes Cancer 2019; 58: 139-148.
- Feurstein S, Thomay K, Hofmann W, Buesche G, Kreipe H, Thol F, Heuser M, Ganser A, Schlegelberger B, Gohring G. Routes of Clonal Evolution into Complex Karyotypes in Myelodysplastic Syndrome Patients with 5q Deletion. Int J Mol Sci 2018: 19(10).
- Behrens YL, Thomay K, Hagedorn M, Ebersold J, Henrich L, Nustede R, Schlegelberger B, Göhring G. Comparison of different methods for telomere length measurement in whole blood and blood cell subsets: Recommendations for telomere length measurement in hematological diseases. Genes Chromosomes Cancer. 2017; 56(9):700-708
- Koenecke C*, Gohring G* (shared first authorship), de Wreede LC, van Biezen A, Scheid C, Volin L, Maertens J, Finke J, Schaap N, Robin M, Passweg J, Cornelissen J, Beelen D, Heuser M, de Witte T, Kroger N, EBMT, M.D.S.s.o.t.C.M.W.P.o.t. Impact of the revised International Prognostic Scoring System, cytogenetics and monosomal karyotype on outcome after allogeneic stem cell transplantation for myelodysplastic syndromes and secondary acute myeloid leukemia evolving from myelodysplastic syndromes: a retrospective multicenter study of the European Society of Blood and Marrow Transplantation. Haematologica 2015; 100: 400-8.
- Woll PS, Kjällquist U, Chowdhury O, Doolittle H, Wedge DC, Thongjuea S, Erlandsson R, Ngara M, Anderson K, Deng Q, Mead AJ, Stenson L, Giustacchini A, Duarte S, Giannoulatou E, Taylor S, Karimi M, Scharenberg C, Mortera-Blanco T, Macaulay IC, Clark SA, Dybedal I, Josefsen D, Fenaux P, Hokland P, Holm MS, Cazzola M, Malcovati L, Tauro S, Bowen D, Boultwood J, Pellagatti A, Pimanda JE, Unnikrishnan A, Vyas P, Göhring G, Schlegelberger B, Tobiasson M, Kvalheim G, Constantinescu SN, Nerlov C, Nilsson L, Campbell PJ, Sandberg R, Papaemmanuil E, Hellström-Lindberg E, Linnarsson S, Jacobsen SE. Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell 2014; 13, 27(4): 603-5.
- Gohring G, Lange K, Hofmann W, Nielsen KV, Hellstrom-Lindberg E, Roy L, Morgan M, Kreipe H, Busche G, Giagounidis A, Schlegelberger B. Telomere shortening, clonal evolution and disease progression in myelodysplastic syndrome patients with 5q deletion treated with lenalidomide. Leukemia 2012; 26: 356-8.
- Göhring G, Giagounidis A, Büsche G, Hofmann W, Kreipe HH, Fenaux P, Hellström-Lindberg E, Schlegelberger B. Cytogenetic follow-up by karyotyping and fluorescence in situ hybridization: implications for monitoring patients with myelodysplastic syndrome and deletion 5q treated with lenalidomide. Haematologica 2011; 96:319-22.
- Gohring G, Michalova K, Beverloo HB, Betts D, Harbott J, Haas OA, Kerndrup G, Sainati L, Bergstraesser E, Hasle H, Stary J, van den Heuvel-Eibrink MM, Zecca M, Fischer A, Noellke P, Strahm B, Locatelli F, Niemeyer CM, Schlegelberger B. Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome. Blood 2010; 116: 3766-9.
- Stein S, Ott MG, Schultze-Strasser S, Jauch A, Burwinkel B, Kinner A, Schmidt M, Krämer A, Schwäble J, Glimm H, Koehl U, Preiss C, Ball C, Martin H, Göhring G, Schwarzwaelder K, Hofmann WK, Karakaya K, Tchatchou S, Yang R, Reinecke P, Kühlcke K, Schlegelberger B, Thrasher AJ, Hoelzer D, Seger R, von Kalle C, Grez M. Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med. 2010; 16:198-204.
- Tehranchi R, Woll PS, Anderson K, Buza-Vidas N, Mizukami T, Mead AJ, Astrand-Grundstrom I, Strombeck B, Horvat A, Ferry H, Dhanda RS, Hast R, Ryden T, Vyas P, Gohring G, Schlegelberger B, Johansson B, Hellstrom-Lindberg E, List A, Nilsson L, Jacobsen SE. Persistent malignant stem cells in del(5q) myelodysplasia in remission. The New England journal of medicine 2010; 363:1025-37.
- Damm F, Lange K, Heuser M, Oberacker T, Morgan M, Wagner K, Krauter J, Schlegelberger B, Ganser A, Gohring G. Phosphoinositide phospholipase Cbeta1 (PI-PLCbeta1) gene in myelodysplastic syndromes and cytogenetically normal acute myeloid leukemia: not a deletion, but increased PI-PLCbeta1 expression is an independent prognostic factor. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2010; 28:e384-7.