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Division of Cellular and Molecular Pathology
Lab Block Level 3
Box 231
Addenbrooke's Hospital
Cambridge
CB2 0QQ
Websites:
Research themes
Division
Research Interests
Mechanisms of Lymphomagenesis
Lymphoma is a heterogeneous disease class consisting of greater than 30 different sub-types and the incidence of this disease has been increasing year on year. In our research we are making progress towards understanding how and why lymphoma develops and hence in the development of new treatments. We investigate a paradigm of lymphomageneis in which a chromosomal translocation leads to the generation of an oncogene and subsequent presumed transformation of T-cells. The oncogene we work with is Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK), a hyperactive tyrosine kinase generated as a result of a translocation between chromosomes 2 and 5. This event is associated with greater than 90% of cases diagnosed as anaplastic large cell lymphoma (ALCL), a mature T-cell malignancy mainly occurring in paediatric patients.
Our research aims to unravel the events leading from the t(2;5) to lymphoma. We use a variety of experimental approaches to reach this goal.
We collaborate with Dr Amos Burke, a paediatric oncologist at Addenbrooke's hospital in Cambridge
- Group Members:
Leila Jahangiri (research associate), Tim Malcolm (research associate), Gavin Garland (research associate), Ricky Trigg (research associate), Liam Lee (PhD student), Camilla Fairbairn (PhD student) Sorcha Forde (PhD student), Hugo Larose (PhD student), Nina Prokoph (PhD student) and Stephen Ducray (PhD student), Jamie Matthews (PhD student).
Other responsibilities:
Organiser Part 1B Pathology
Fellow and Tutor Hughes Hall
Executive committee member and co-lead paediatric programme, Cambridge Cancer Centre
Coordinator ALKATRAS Marie Curie Innovative Training Network (www.alkatras.erialcl.net)
Biological studies lead, NCRI paediatric lymphoma clinical studies sub-group
Co-chair European Inter-group for Childhood Non-Hodgkin Lymphoma (EICNHL)
Key Publications
1. Malcolm, T*., Villarese, P*., Fairbairn, C., Lamant, L., Trinquand, A., Hook, C.E., Burke, G.A.A., Brugieres, L., Hughes K., Payet, D., Merkel, O., Schiefer, A., Ashankyty, I., Mian, S., Wasik, M., Turner, M., Kenner, L., Asnafi, V., Macintyre,E. and Turner, S.D. (2015) NPM-ALK mimics beta selection enabling thymic escape and peripheral lymphoma development. Nature Communications, 7, Article number: 10087 doi:10.1038/ncomms10087
2. Ceccon M., Boggio Merlo E., Mologni L., Poggio T., Varesio L.M., Menotti M., Bombelli S., Rigolio R., Manazza A.D., Ambrogio C., Giudici G., Casati C., Mastini C., Compagno M., Turner S.D., Gambacorti-Passerini C., Voena C. and Chiarle R. (2015) Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency. Oncogene, doi: 10.1038/onc.2015.456
3. Pencik, J., Schlederer, M., Gruber, W., Aberger, F., Kennedy, R., Walker, S.M., Malcolm, T., Turner, S.D., Rose-John, S., Chalaris, A., Levy, D.E., Marié, I.J., Hassler, M.R., Poli, V., Unger, C., Eferl, R., Esterbauer, H., Aksoy, O., Tahereh, J., Skucha, A., Grebien, F., Herac, M., Mazal, P., Haitel, A., Susani, M., Moriggl, R., Dolznig, H., Culig, Z.& Kenner, L.(2015) Loss of IL-6/Stat3 signaling drives prostate cancer progression in mice and men. Nature Communications Jul 22;6:7736. doi: 10.1038/ncomms8736.
4. Merkel, O., Hamacher, F., Griessl, R., Grabner, L., Schmatz, A., Prutsch, N., Baer, C., Hartmann, T., Simonitsch, I., Plass, C., Turner, S.D., Zenz, T., Greil, R. and Kenner, L. (2015) Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation. J. Path in press.
5. Moti, N., Malcolm, T., Hamoudi, R., Mian, S., Garland, G., Hook, C.E., Burke, G.A.A., Wasik, M., Merkel, O., Kenner, L., Laurenti, E., Dick, J.E.and Turner, S.D. (2014) Anaplastic Large Cell Lymphoma stem cells possess a gene expression profile reflective of an early thymic progenitor pointing to a primitive cell of origin. Oncogene, doi:10.1038/onc.2014.112
6. Marzec M., Halasa K., Liu X., Cheng M., Baldwin D., Tobias J.W., Schuster S., Woetmann A., Turner S.D., Odum N., and Wasik M.A. (2013)Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2- induced cell signaling and gene expression reprogramming. Journal of Immunology 191(12):6200-7
7. McDuff, F.K.E., Lim, S-V., Dalbay, M. and Turner, S.D. (2013) Assessment of the transforming potential of novel Anaplastic Lymphoma Kinase point mutants. Molecular Carcinogenesis 52(1):79-83
8. Laimer, D., Dolznig, H., Kollmann, K., Vesely, P.W., Schlederer, M., Merkel, O., Schiefer, A., Hassler, M.R., Heider, S., Amenitsch, L., Thallinger, C., Staber, P.B., Simonitsch-Klupp, I., Artaker, M., Lagger, S., Turner, S.D., Pileri, S., Piccaluga, P.P., Valent, P., Messana, K., Landra, I., Weichhart, T., Knapp, S., Shehata, M., Todaro, M., Sexl, V., Höfler, G., Piva, R., Medico, E., Riggeri, B.A., Cheng, M., Eferl, R., Egger, G., Penninger, J.M., Jaeger, U., Moriggl, R., Inghirami, G.and Kenner, L. (2012) Identification of PDGFR blockade as a rational and highly effective therapy for NPM-ALK driven lymphomas. Nature Medicine 18(11):1699-704
9. Zhang, Q., Wang, HY., Kantekure, K., Paterson, JC., Liu, X., Schaffer, A., Paulos, C, Milone, MC., Odum, N., Turner, SD., Marafioti, T., Wasik, MA. (2011) Oncogenic tyrosine kinase NPM-ALK induces expression of the growth-promoting receptor ICOS. Blood 118(11):3062-71.
10. Martinelli, P., Bonetti, P., Sironi, C., Pruneri, G., Fumagalli, C., Raviele, PR., Volorio, S., Pileri, S., Chiarle, R., Khoramian Tusi, B., McDuff, F.K.E., Turner, S.D., Inghirami, G., Pelicci, P.G. and Colombo, E. (2011) The lymphoma-associated NPM-ALK oncogene elicits a p16INKa/pRb-dependent tumour-suppressive pathway. Blood 117(24):6617-26.
11. McDuff F.K.E., Hook C.E., Tooze R., Huntly B.J. Pandolfi P.P. and Turner S.D. (2011) Determining the Contribution of NPM1 heterozygosity to NPM-ALK-induced lymphomagenesis. Lab Investigation doi: 10.1038/labinvest.2011.96
12. McDuff F.K.E and Turner S.D. (2011) Aberrant Anaplastic Lymphoma Kinase Activity Induces a p53 and Rb-Dependent Senescence-Like Arrest in the Absence of Detectable p53 Stabilization. PLOS One 6(3): e17854. doi:10.1371/journal.pone.0017854
13. Merkel, O., Hamacher, F., Laimer, D., Scheideler, M., Trajanoski, Z., Egger, G., Turner, SD., Greil, R. and Kenner, L. (2010) Diacritic and functionally active microRNAs in both ALK+ and ALK- ALCL. PNAS 107(37):16228-33
14. Youssif, C., Goldenbogan J., Hamoudi R., Viskaduraki M., Bacon, CM, Burke, A.A and Turner S.D. (2009) Genomic profiling of pediatric ALK-positive Anaplastic Large Cell Lymphoma – a Children’s Cancer and Leukaemia Group study. Genes Chromosomes and Cancer 48(11):1018-26
15. Rigby S., Huang Y., Streubel B., Chott A., Du M-Q., Turner S.D. and Bacon C.M. (2009) The lymphoma associated fusion tyrosine kinase Itk-Syk requires Pleckstrin homology domain-mediated membrane localization for activation and cellular transformation. JBC 284(39):26871-81
16. Cui Y., Kerby A., McDuff F.K.E. and Turner S.D. (2009) NPM-ALK modulates the p53 tumour suppressor pathway in a JNK and PI 3-Kinase dependent manner: MDM-2 is a potential therapeutic target for the treatment of ALK-expressing malignancies. Blood. 113(21):5217-5227.
17. Turner S.D., Yeung D., Hadfield K., Cook S.J. and Alexander D.R. (2007) The NPM- ALK Tyrosine Kinase Mimics TCR Signalling Pathways Inducing NFAT and AP-1 by Ras-Dependent Mechanisms. Cellular Signaling. 19(4):740-47.
18. Turner S.D., Merz H., Yeung D., Alexander D.R. (2006) CD2 Promoter Regulated Nucleophosmin-Anaplastic Lymphoma Kinase in Transgenic Mice Causes B Lymphoid Malignancy. Anticancer Research 26(5A):3275-79.
19. Turner S.D., Tooze R.M., Macklennan K., Alexander D.R. (2003) Vav-promoter regulated oncogenic fusion protein NPM-ALK in transgenic mice causes B-cell lymphomas with hyperactive Jun kinase. Oncogene 22:7750-7761.