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.
Subject(s)
Cell Proliferation , Fusion Proteins, bcr-abl/metabolism , Gene Expression Regulation, Leukemic , Leukemia/pathology , Telomere/ultrastructure , Animals , Apoptosis , Bone Marrow Cells/cytology , Cell Cycle , Cell Line, Tumor , Cellular Senescence , Chemokines/metabolism , Cytokines/metabolism , Disease Progression , Humans , Inflammation/metabolism , Leukemia/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , PhenotypeABSTRACT
Different designs of functional knee braces for ACL-injury rehabilitation exist. In addition to the mechanical stabilization provided by rigid shell braces, sleeve braces also address proprioceptive mechanisms, but little is known if this leads to benefits for ACL-deficient subjects. Therefore the aim of this study was to investigate the effect of 2 different functional brace designs (shell and sleeve brace) on functional achievements in ACL-deficient patients. 28 subjects with ACL-ruptured knees performed tests for knee joint laxity, joint position sense, static and dynamic balance and isometric and dynamic lower limb extension strength in non-braced, sleeve braced and shell braced condition. The results showed a significant decrease in knee joint laxity for sleeve (33%; p<0.001) and rigid shell bracing (14%, p=0.039). The sleeve brace revealed a significant increase in dynamic balance after perturbation (20%; p=0.024) and a significant increase in dynamic lower limb peak rate of force development (17%; p=0.015) compared to the non-braced condition. The effects might be caused by the flexible area of support and the incorporated mechanisms to address proprioceptive aspects. Braces might not be needed in simple daily life tasks, but could provide beneficial support in more dynamic settings when patients return to sporting activities after an ACL-injury.