title: A 'telomere-associated secretory phenotype' cooperates with BCR-ABL to drive malignant proliferation of leukemic cells.
abstract: Telomere biology is frequently associated with disease evolution in human cancer and dysfunctional telomeres have been demonstrated to contribute to genetic instability. In BCR-ABL(+) chronic myeloid leukemia (CML), accelerated telomere shortening has been shown to correlate with leukemia progression, risk score and response to treatment. Here, we demonstrate that proliferation of murine CML-like bone marrow cells strongly depends on telomere maintenance. CML-like cells of telomerase knockout mice with critically short telomeres (CML-iG4) are growth retarded and proliferation is terminally stalled by a robust senescent cell cycle arrest. In sharp contrast, CML-like cells with pre-shortened, but not critically short telomere lengths (CML-G2) grew most rapidly and were found to express a specific 'telomere-associated secretory phenotype', comprising secretion of chemokines, interleukins and other growth factors, thereby potentiating oncogene-driven growth. Moreover, conditioned supernatant of CML-G2 cells markedly enhanced proliferation of CML-WT and pre-senescent CML-iG4 cells. Strikingly, a similar inflammatory mRNA expression pattern was found with disease progression from chronic phase to accelerated phase in CML patients. These findings demonstrate that telomere-induced senescence needs to be bypassed by leukemic cells in order to progress to blast crisis and provide a novel mechanism by which telomere shortening may contribute to disease evolution in CML.
authors.affiliation: 1] Department of Oncology/Hematology and Bone Marrow Transplantation with Section of Pneumology, Hubertus Wald Tumor-Zentrum, University Hospital Hamburg-Eppendorf, Hamburg, Germany [2] Division of Hematology, University Hospital Zürich, Zürich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Braig
authors.affiliation: Department of Oncology/Hematology and Bone Marrow Transplantation with Section of Pneumology, Hubertus Wald Tumor-Zentrum, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Pällmann
authors.affiliation: Department of Oncology/Hematology and Bone Marrow Transplantation with Section of Pneumology, Hubertus Wald Tumor-Zentrum, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Preukschas
authors.affiliation: Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Steinemann
authors.affiliation: Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Hofmann
authors.affiliation: Institute of Molecular Medicine and Max-Planck-Research Group on Stem Cell Aging, Ulm, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Gompf
authors.affiliation: Institute of Clinical Chemistry, University Hospital Cologne, Cologne, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Streichert
authors.affiliation: Department of Pathology, University Hospital of the RWTH Aachen, Aachen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Braunschweig
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Scotland, UK.
authors.forename: M
authors.initials: M
authors.lastname: Copland
authors.affiliation: Leibniz Institute of Age Research - Fritz-Lipmann Institute (FLI), Jena, Germany.
authors.forename: K L
authors.initials: KL
authors.lastname: Rudolph
authors.affiliation: Department of Oncology/Hematology and Bone Marrow Transplantation with Section of Pneumology, Hubertus Wald Tumor-Zentrum, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: Department of Hematology and Oncology, University Hospital of the RWTH Aachen, Aachen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Koschmieder
authors.affiliation: Aachen Institute for Advanced Study in Computational Engineering Science (AICES), RWTH Aachen University, Aachen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schuppert
authors.affiliation: 1] Department of Oncology/Hematology and Bone Marrow Transplantation with Section of Pneumology, Hubertus Wald Tumor-Zentrum, University Hospital Hamburg-Eppendorf, Hamburg, Germany [2] Division of Hematology, University Hospital Zürich, Zürich, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Balabanov
authors.affiliation: Department of Hematology and Oncology, University Hospital of the RWTH Aachen, Aachen, Germany.
authors.forename: T H
authors.initials: TH
authors.lastname: Brümmendorf
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D016615:Telomere / Q000648:ultrastructure*
chemical_list: D018925:Chemokines; D016207:Cytokines; D016044:Fusion Proteins, bcr-abl