A 'telomere-associated secretory phenotype' cooperates with BCR-ABL to drive malignant proliferation of leukemic cells

Braig, M. et al. (2014) A 'telomere-associated secretory phenotype' cooperates with BCR-ABL to drive malignant proliferation of leukemic cells. Leukemia, 28(10), pp. 2028-2039. (doi: 10.1038/leu.2014.95) (PMID:24603533)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Copland, Professor Mhairi
• Authors: Braig, M., Pällmann, N., Preukschas, M., Steinemann, D., Hofmann, W., Gompf, A., Streichert, T., Braunschweig, T., Copland, M., Rudolph, K.L., Bokemeyer, C., Koschmieder, S., Schuppert, A., Balabanov, S., and Brümmendorf, T.H.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Leukemia
• Publisher: Nature Publishing Group
• ISSN: 0887-6924
• ISSN (Online): 1476-5551