Research
In our lab, we investigate the pathogenesis and aetiology of paediatric cancers towards the development of biomarkers to facilitate kinder, less toxic and novel therapeutic approaches.
Mechanisms of Lymphomagenesis
Lymphoma is a heterogeneous disease class consisting of greater than 40 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.
Understanding drug resistance in paediatric cancers
We are also developing a resource of patient derived xenografts of paediatric lymphoma, specifically ALCL and Burkitt lymphoma as well as neuroblastoma. Applying these models, our lab is conducting research to experimentally-induce relapse in an effort to understand clonal evolution of tumour cell growth. With this knowledge in hand, our lab then applies high-throughput drug screens and sequencing approaches to develop novel therapeutic regimens. Alongside, this research activity, we also employ CRISPR/Cas9 screens for the identification of putative mechanisms of drug resistance employing cell lines.
Comparative analysis of endemic and sporadic Burkitt lymphoma
Our lab works together with Jackson Orem at the Uganda Cancer Institute in Kampala, Uganda in an effort to understand the aetiology and pathogenesis of Burkitt lymphoma with a particular emphasis on tumour clonal evolution with treatment. This aspect of our research is supported by Cambridge Africa.
Breast implant associated anaplastic large cell lymphoma (BIA-ALCL)
The most recent addition to the family of ALCL is a form of cancer associated with the presence of textured breast implants. Given our 20 years of experience of working towards understanding the pathogenesis of ALCL, we have turned our attention to unraveling the mechanisms that drive this specific form of cancer.
Group Members:
- Jamie Matthews
- Mun Liew
- Perla Pucci
- Lucy Hare
- Emily James
- Gill Currie
We collaborate with Dr Amos Burke, a paediatric oncologist at Addenbrooke's hospital in Cambridge
Other responsibilities:
Chair of the graduate education committee of the department of 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
Chair of the European Research Initiative for ALK-related malignancies (ERIA; www.erialcl.net)
Co-chair European Inter-group for Childhood Non-Hodgkin Lymphoma (EICNHL)
Member MHRA PRASEAG and EU SCHEER committees regarding breast implants and lymphoma risk.
Publications
A full list of publications can be found via ORCID ID: https://orcid.org/0000-0002-8439-4507
Forde, S., Matthews, J.D., Jahangiri, L., Lee, L.C., Malcolm, T.I., Bell, N., Bomken, S., Burke, G.A.A., and Turner, S.D. (2020) Paediatric Burkitt lymphoma patient-derived xenografts capture disease characteristics over time and are a model for therapy, British Journal of Haematology, http://dx.doi.org/10.1111/bjh.17043
Prokoph, N., Probst, N.A., Lee, L.C., Monahan, J.M., Malik, V., Liang, H-C., Sharma, G.G., Montes-Mojarro, I., Mota, I., Larose, H., Forde, S.D., Imamoglu, R., Matthews, J.D., Trigg, R., Ceccon, M., Ducray, S.P., Lobello, C., Janikova, A., Gambacorti-Passerini, C., Pospisilova, S., Kenner, L., Klapper, W., Jauch, R., Woessmann, W., Chiarle, R., Mologni, L., Merkel, O., Brugières, L., Geoerger, B., Barbieri, I., and Turner, S.D. (2020) Inflammatory networks drive resistance to drugs in ALCL, ALK+; the IL10R is up-regulated in response to consistent exposure to ALK inhibition. Blood, In press
Larose, H., Prokoph, N., Mian, S., Nuglozeh, E., Fazaludeen, F.M.S., Elmouna, A., Ashankyty, I., Mologni, L., Gambacorti-Passerini, C., Ming-Qing Du1, Hoefler, G., Pospisilova, S., Woessmann, W., Blundell, T., Ali., Damm-Welk, C., Fedorova, A., Lamant, L., Schlederer, M., Kenner, L., Merkel O. and Turner, S.D (2020) A novel mutation in Notch1 contributes to the pathogenesis of ALCL. Haematologica, in press
Klingeberg, C., Kreutmair, S., Poggio, T., Keller, A., Andrieux, G., Miething, C., Follo, M., Pfeifer, D., Lengerke, C., Fend, F., Qintanilla de Fend, L., Zeiser, R., Turner, S.D., Boerries, M., Duyster, J. and Illert, A.L. (2019) Existence of reprogrammed lymphoma initiating cells in a murine ALCL model. Leukemia, in press
Trigg, R.M., Shaw, J.A. and Turner, S.D. (2019) Opportunities and challenges of circulating biomarkers in neuroblastoma. Open Biology, 9(5):190056. doi: 10.1098/rsob.190056
Fritzal, F., Turner, S.D.* and Kenner, L.* (2019) Is Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) a Hazard of Breast Implant Surgery? Open Biology, 9(4):190006. doi: 10.1098/rsob.190006
Turner, S.D. (2019) Anaplastic Large Cell Lymphoma: chapter in Non-Hodgkin Lymphoma in Childhood and Adolescence, Springer International Publishing DOI: 10.1007/978-3-030-11769-6, eBook ISBN: 978-3-030-11769-6, Hardcover ISBN:978-3-030-11768-9
Larose, H., Burke, G.A.A., Lowe, E. and Turner, S.D. (2019) From Bench to Bedside: The past, present and future of therapy for systemic paediatric ALCL, ALK+ British Journal of Haematology, doi: 10.1111/bjh.15763.
Trigg, R.M.,* Lee, L.C.,* Prokoph, N.,* Jahangiri, L., Reynolds C.P., Burke, G.A.A., Probst, N.A., Han, M., Matthews, J.D., Lim, K.K., Manners, E., Martinez, S., Pastor, J., Blanco-Aparicio, C., Merkel, O., Garces de los Fayos Alonso, I., Kodajova, P., Tangermann, S., Högler, S., Luo, J., Kenner, L.* and Turner, S.D.* (2019) PIM1 inhibition enhances the sensitivity of high-risk aberrant 1 ALK-expressing neuroblastoma to ALK inhibition regardless of MYCN status. Nature Communications, DOI: 10.1038/s41467-019-13315-x
This publication was highlighted as an ‘editor’s choice’ in Science Translational Medicine: Joan Montero, (2019) A new hope for neuroblastoma treatment? Science Translational Medicine 11, 523, eaaz9769 DOI: 10.1126/scitranslmed.aaz9769
Haque, M., Li,J., Huang, Y-H., Almowaled, M., Barger, C.J., Karpf,A.R., Wang, P., Chen, W., Turner, S.D. and Lai, R. (2019) NPM-ALK is a key regulator of the oncoprotein FOXM1 in ALK-positive anaplastic large cell lymphoma: identification of a novel role for NPM1 in the pathobiology of NPM-ALK. Cancers, 11(8). pii: E1119. doi: 10.3390/cancers11081119
Prutsch, N., Suske, T., Liang, H.C., Wu, L., Simonitsch- Klupp, I., Alvarez-Hernandez, A., Gurnhofer, E., Schlederer, M., Roos, S., Kornauth, C., Leone, D., Aufinger, A., Hielscher, T., Aberger, F., Stoiber, D., Strobl, B., Müller, M., Jäger, U., Staber, P., Grebien, F., Moriggl, R., Inghirami, G., Sanda, T., Look, A.T., Turner, S.D., Kenner, L. and Merkel, O. (2018) Dependency on the TYK2/STAT1/MCL1 axis in Anaplastic Large Cell Lymphoma. Leukemia Mar;33(3):696-709. doi: 10.1038/s41375-018-0239-1.
Schleussner, N., Merkel, O., Hummel, F., Costanza, M., Huan-Chang Liang, H-C., Romagnani, C., Durek, P., Anagnostopoulos, I., Hummel, M., Jöhrens, K., Niedobitek., A, Griffin, P.R., Woessmann, W., Damm-Welk, C., Hinze, C., Stoiber, D., Gillissen, B., Turner, S.D., Kaergel, E., von Hoff, L., Grau, M., Lenz, G., Dörken, B., Scheidereit, C., Kenner, L., Janz, M., and Mathas, S. (2017) The AP-1 -BATF and -BATF3 module is essential for growth, survival and TH17 / ILC3 skewing of anaplastic large cell lymphoma. Leukemia 32: 1994–2007 doi: 10.1038/s41375-018-0045-9
Johnson, L., O’Donoghue, J.M., McLean, N., Turton, P., Khan, A.A., Turner, S.D., Lennard, A., Collis, N., Butterworth, M., Gui, G., Bristol, J., Hurren, J., Smith, S., Grover, K., Spyrou, G., Krupa, K., Azmy, I.A., Young, I.E., Staiano, H., Khalil J.J., and MacNeill, F.A. (2017) Breast Implant Associated Anaplastic Large Cell Lymphoma: The UK experience. Recommendations on its management and implications for informed consent. European Journal of Surgical Oncology Aug;43(8):1393-1401. doi: 10.1016/j.ejso.2017.05.004
Hassler, M.R., Pulverer, W., Redl, E., Hacker, J., Garland, G., Schiefer, A., Simonitsch-Klupp, I., Kenner, L., Weinhäusel, A., Turner, S.D. and Egger, G. (2016) ALK-dependent transcription factor networks are associated with epigenomic alterations of DNA methylation in ALCL. Cell Reports 17(2):596-608. doi: 10.1016/j.celrep.2016.09.018
Damm-Welk C., Fischer M., Narayanan V, Camidge R., Harris M., Siddiqi F., Burke G.A.A., Lehrnbecher T., Pulford K., Oschlies I., Siebert R., Turner SD* and Woessmann W*. (2016) Anti-ALK-antibodies in patients with ALK-positive malignancies not expressing NPM-ALK. Journal of Cancer, 7(11): 1383-1387.
Malcolm, T., Hodson, D.J., Macintrye E.A. and Turner, S.D. (2016) Challenging perspectives on the cellular origin of lymphoma. Open Biology, 6(9). pii: 160232
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. (2016) NPM-ALK mimics beta selection enabling thymic escape and peripheral lymphoma development. Nature Communications, 7, Article number: 10087 doi:10.1038/ncomms10087
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
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 Aug;236(4):445-56. doi: 10.1002/path.4539.
Turner, S.D., Lamant, L., Kenner, L. and Brugieres, L. (2015) Anaplastic Large Cell lymphoma: biology and clinical application. British Journal of Haematology, 173(3):560-72, doi: 10.1111/bjh.13958.
Ye X., Shokrollahi K., Rozen W.M., Whitaker I.S.,* and Turner S.D.* (2014) Anaplastic Large Cell Lymphoma (ALCL) and Breast Implants: Breaking down the evidence *joint corresponding authors. Mutation Research – Reviews, 762C:123-132.
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, Apr 2;34(14):1843-52. doi: 10.1038/onc.2014.112
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
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.
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
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
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.
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.
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.
