AG Genetics of Myeloid Neoplasia

​​​Myeloid neoplasms (for example, myelodysplastic syndrome [MDS] and acute myeloid leukemia [AML]) are cancers of the hematopoietic system with a wide spectrum of clinical presentations: they occur in young adults or even children, but more frequently affect older persons or patients who have received chemotherapy or radiation treatment for another cancer. While some patients with MDS have a benign clinical course over many years, and some AML patients are cured by chemotherapy or stem cell transplantation, others have aggressive disease and many patients still die of their disease.

Understanding the genetic and epigenetic factors that underlie this heterogeneous presentation has been the focus of our work over the past 10 years. Using modern high-throughput sequencing methods, we comprehensively defined the spectrum and prognostic relevance of driver gene mutations in AML and identified distinct genetic subsets of this disease. These genetic analyses also uncovered that overt myeloid neoplasms such as MDS and AML are often preceded by a 'pre-leukemia' phase where patients still have relatively normal blood counts and no symptoms, while some of their blood cells already carry clonal somatic genetic alterations also found in AML and MDS.

Meanwhile, it has become clear that this phenomenon, called ‚clonal hematopoiesis' (CH), is in fact very common among elderly persons: Among elderly individuals with no hematological disease aged ≥70 years, CH can be identified in over 40%. Importantly, recent studies have shown that mutant blood cell clones in persons with CH associate with inflammatory diseases, including vascular inflammation and atherosclerosis. These recent developments move early clonal alterations of hematopoiesis into the spotlight: they are not only precursor stages of rare types of blood cancer, but in fact represent a very common age-associated phenomenon with direct pathophysiological links to common diseases such myocardial infarction, stroke and autoimmune disease.

Therefore, understanding the genetic mechanisms that drive evolution of myeloid neoplasia from the earliest steps of clonal hematopoiesis to overt myeloid neoplasia, as well as further changes occurring during and after treatment, is at the center of our current translational research projects.

Methodologically, we use state of the art genomics techniques including next-generation sequencing, nanopore sequencing, single-cell analyses, digital droplet PCR and cell-free nucleic acid analyses, in a patient-centered approach. Our work is based on close interactions with our diagnostic laboratory, national and international study groups (e.g. the German MDS study group D-MDS) and our national and international collaborators.

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Projects for MD theses are also available – please inquire via email (klaus.metzeler@medizin.uni-leipzig.de).

Selected References:

Hecker JS, Hartmann L, Rivière J, Buck MC, van der Garde M, Rothenberg-Thurley M, Fischer L, Winter S, Ksienzyk B, Ziemann F, Solovey M, Rauner M, Tsourdi E, Sockel K, Schneider M, Kubasch AS, Nolde M, Hausmann D, Paulus AC, Lützner J, Roth A, Bassermann F, Spiekermann K, Marr C, Hofbauer LC, Platzbecker U, Metzeler KH, Götze KS. CHIP and hips: clonal hematopoiesis is common in patients undergoing hip arthroplasty and is associated with autoimmune disease. Blood. 2021 Nov 4;138(18):1727-1732. doi: 10.1182/blood.2020010163 . PMID: 34139005.​

Rausch C, Rothenberg-Thurley M, Buerger SA, Tschuri S, Dufour A, Neusser M, Schneider S, Spiekermann K, Metzeler KH, Ziemann F. Double Drop-Off Droplet Digital PCR: A Novel, Versatile Tool for Mutation Screening and Residual Disease Monitoring in Acute Myeloid Leukemia Using Cellular or Cell-Free DNA. J Mol Diagn. 2021 Aug;23(8):975-985. doi: 10.1016/j.jmoldx.2021.05.001 . Epub 2021 May 19. PMID: 34020042.​

Herold T, Rothenberg-Thurley M, Grunwald VV, Janke H, Goerlich D, Sauerland MC, Konstandin NP, Dufour A, Schneider S, Neusser M, Ksienzyk B, Greif PA, Subklewe M, Faldum A, Bohlander SK, Braess J, Wörmann B, Krug U, Berdel WE, Hiddemann W, Spiekermann K, Metzeler KH. Validation and refinement of the revised 2017 European LeukemiaNet genetic risk stratification of acute myeloid leukemia. Leukemia. 2020 Dec;34(12):3161-3172. doi: 10.1038/s41375-020-0806-0 . Epub 2020 Mar 30. PMID: 32231256; PMCID: PMC7685975. ​

Rothenberg-Thurley M, Amler S, Goerlich D, Köhnke T, Konstandin NP, Schneider S, Sauerland MC, Herold T, Hubmann M, Ksienzyk B, Zellmeier E, Bohlander SK, Subklewe M, Faldum A, Hiddemann W, Braess J, Spiekermann K, Metzeler KH. Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia. Leukemia. 2018 Jul;32(7):1598-1608. doi: 10.1038/s41375-018-0034-z . Epub 2018 Feb 23. PMID: 29472724; PMCID: PMC6035153. ​

Metzeler KH, Herold T, Rothenberg-Thurley M, Amler S, Sauerland MC, Görlich D, Schneider S, Konstandin NP, Dufour A, Bräundl K, Ksienzyk B, Zellmeier E, Hartmann L, Greif PA, Fiegl M, Subklewe M, Bohlander SK, Krug U, Faldum A, Berdel WE, Wörmann B, Büchner T, Hiddemann W, Braess J, Spiekermann K; AMLCG Study Group. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016 Aug 4;128(5):686-98. doi: 10.1182/blood-2016-01-693879​ . Epub 2016 Jun 10. PMID: 27288520.​