Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation
Krenn, Peter William
Hartmann, Tanja Nicole
Journal of Pathology
Wiley on behalf of the Pathological Society of Great Britain and Ireland
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Merkel, O., Hamacher, F., Griessl, R., Grabner, L., Schiefer, A., Prutsch, N., Baer, C., et al. (2015). Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation. Journal of Pathology, 236 445-456. https://doi.org/10.1002/path.4539
Anaplastic large cell lymphoma (ALCL) is a rare, aggressive non-Hodgkin lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion protein (ALCL, ALK+). However, little is known about the molecular features and tumor drivers in ALK negative ALCL (ALCL, ALK-), which is characterized by a worse prognosis. We show that ALCL, ALK- in contrast to ALK+ lymphomas display high miR-155 expression. In line, we observe an inverse correlation between miR-155 promoter methylation and miR-155 mRNA expression in ALCL. ALK kinase activity has no direct effect on miR-155 levels. Ago2 immunoprecipitation reveals miR-155 as the most abundant miRNA in the Ago2 complex in ALCL, ALK-. To investigate its function in T-cell lymphoma we have over-expressed miR-155 in ALCL, ALK+ cell lines and demonstrate reduced levels of the target protein C/EBPβ. In murine engraftment models of ALCL, ALK-, we show that anti-miR-155 mimics are able to reduce tumor growth. This goes hand in hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumors, which leads to suppression of STAT3 signaling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPβ target IL-8. These data suggest that miR-155 can act as a tumor driver in ALCL, ALK- and blocking miR-155 could be therapeutically relevant.
This work was supported by the SCRI-LIMCR GmbH, the “Jubiläumsfond der Österreichischen Nationalbank” (grant-no. 14856 to O.M.), R.G. was supported by grant SFB P021 from the Austrian Science Funds (FWF), L.K. was supported by grant FWF, P26011, R.M. was supported by FWF grants SFB F28 and SFB F47. S.D.T. is a Senior Lecturer supported with funding from Leukemia and Lymphoma Research.
External DOI: https://doi.org/10.1002/path.4539
This record's URL: https://www.repository.cam.ac.uk/handle/1810/248967
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/