title: Telomere dynamics in patients with del (5q) MDS before and under treatment with lenalidomide.
abstract: Myelodysplastic syndrome (MDS) associated with an acquired, isolated deletion of chromosome 5q (del (5q) MDS), represent a clonal disorder of hematopoiesis and a clinically distinct entity of MDS. Treatment of del (5q) MDS with the drug lenalidomide has significantly improved quality of life leading to transfusion independence and complete cytogenetic response rates (CCR) in the majority of patients. Telomeres are located at the end of eukaryotic chromosomes and are linked to replicative history/potential as well as genetic (in) stability of hematopoietic stem cells. Here, we analyzed telomere length (TL) dynamics before and under lenalidomide treatment in the peripheral blood and/or bone marrow of del (5q) patients enrolled in the LEMON-5 study (NCT01081431). Hematopoietic cells from del (5q) MDS patients were characterized by significantly shortened TL compared to age-matched healthy controls. Telomere loss was more accelerated in patients with longer disease duration (>2 years) and more pronounced cytopenias. Sequential analysis under lenalidomide treatment revealed that previously shortened TL in peripheral blood cells was significantly "elongated" towards normal levels within the first six months suggesting a shift from clonal del (5q) cells towards normal hematopoiesis in lenalidomide treated MDS patients. Taken together our findings suggest that the development of the del (5q) clone is associated with accelerated telomere shortening at diagnosis. However, upon induction of CCR and reoccurrence of normal hematopoiesis, the lack of a persistent TL deficit argues against telomere-mediated genetic instability neither as a disease-promoting event of del (5q) MDS nor for lenalidomide mediated development of secondary primary malignancies of the hematopoietic system in responding patients.
authors.affiliation: Telomere and Telomerase Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Department of Hematology, Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany. Electronic address: fbeier@ukaachen.de.
authors.forename: Fabian
authors.initials: F
authors.lastname: Beier
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Behzad Kharabi
authors.initials: BK
authors.lastname: Masouleh
authors.affiliation: Institute for Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Guntram
authors.initials: G
authors.lastname: Buesche
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Monica S
authors.initials: MS
authors.lastname: Ventura Ferreira
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Rebekka K
authors.initials: RK
authors.lastname: Schneider
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ziegler
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wilop
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Lucia
authors.initials: L
authors.lastname: Vankann
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Gattermann
authors.affiliation: Department of Medicine I, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, St Johannes Hospital, Duisburg, Germany.
authors.forename: Aristoteles
authors.initials: A
authors.lastname: Giagounidis
authors.affiliation: Department of Hematology and Oncology, Technical University München, München, Germany.
authors.forename: Katharina S
authors.initials: KS
authors.lastname: Götze
authors.affiliation: Department of Internal Medicine III, University Hospital Mannheim, Mannheim, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Nolte
authors.affiliation: Department of Internal Medicine III, University Hospital Mannheim, Mannheim, Germany.
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.affiliation: Department of Hematology and Oncology, University Hospital Göttingen, Göttingen, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Haase
authors.affiliation: Institute for Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Kreipe
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Panse
authors.affiliation: Telomere and Telomerase Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Germing
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
keywords: Del (5q); Leukemic stem cell; Myelodysplastic syndromes; Telomere