Cross, Nick - University of Southampton

个人简介

Nick Cross read Natural Sciences at Cambridge University and stayed on to do a PhD in the Department of Genetics. He moved to the Hammersmith Hospital in 1987, where he developed an interest in leukaemia. Working initially on the development of quantitative molecular assays to determine the response of patients to therapy, he developed a research programme aimed at understanding the molecular genetics of myeloid neoplasms. This work has resulted more than 250 peer reviewed publications and is continuing in Salisbury, where he relocated in 2001 to take up Directorship of the Wessex Regional Genetics Laboratory and a Chair of Human Genetics at the University of Southampton. In 2002 he led a successful bid to establish one of two National Genetics Reference Laboratories (NGRL), with a focus on the development, validation and standardisation of genetic tests.

研究领域

Nick Cross is interested in the molecular pathogenesis of haematological malignancies, in particular chronic myeloid leukaemia (CML), myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). Analysis of chromosome abnormalities Initially our work focused on the analysis of chromosome translocations which, despite being uncommon, proved to be an important route towards understanding the molecular pathogenesis of myeloid malignancies. We have characterized more than 25 different translocations and found that the majority result in fusion genes encoding chimaeric proteins with an N-terminal region derived from a partner gene fused in frame to the C-terminal region of a tyrosine kinase such as ABL, PDGFRα, PDGFRβ, JAK2, KIT or FGFR1. Tyrosine kinases are excellent drug targets and we are using preclinical models to evaluate the efficacy of novel small molecule inhibitors against activated tyrosine kinases in myeloid disorders. Genomewide genetic profiling Our principal focus has been the use of genomewide profiling techniques to identify novel, somatically acquired genetic abnormalities. We have used comparative genomic hybridisation (CGH) to identify cases with microdeletions, and single nucleotide polymorphism arrays to identify regions of acquired uniparental disomy (aUPD), both of which are associated with critical drivers of oncogenesis. Recently our focus has been on whole exome, whole genome and RNA sequencing to identify novel mutations. Notable achievements to data have been the finding of recurrent mutations in genes encoding the signalling regulator CBL (Grand et al. Blood 2009) the polycomb group protein EZH2 (Ernst et al. Nature Genetics 2010) and SETBP1, the function of which is poorly understood (Piazza et al., Nature Genetics 2012). Several candidate abnormalities and genomic regions are currently under investigation, as is the functional analysis of novel abnormalities. Genetic predisposition to myeloid disorders Many MPN are characterised by the presence of the acquired JAK2 V617F mutation. We made the remarkable finding that this mutation does not arise randomly, but rather it is seen preferentially on a common JAK2 haplotype that we have called 46/1 (Jones et al. Nature Genetics 2009). The molecular basis for this predisposition is under investigation but must presumably be a consequence of increased mutation rates (hypermutability hypothesis) or a functional difference in JAK2 that confers a selective advantage when this gene is mutated (fertile ground hypothesis). We have recently completed a genomewide association study and identified several novel candidate loci that predispose to JAK2 unmutated MPN. Development and standardisation of genetic tests We have had a long standing interest in the development of genetic tests, and one of our main areas of current activity is the standardisation of molecular monitoring of CML patients by qRT- PCR for BCR-ABL mRNA. We have developed primary, World Health Organisation approved reference reagents for BCR-ABL testing (White et al. Blood 2010) and are working with colleagues in Europe and internationally to help improve and standardise laboratories testing for minimal residual disease in CML (Cross et al., Leukemia 2012). Other projects include the development of next generation sequencing based panel tests for a variety of malignant conditions and development of novel sensitive tests to monitor the response of cancer patients to treatment.

近期论文

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Antisense oligonucleotides modulating activation of a nonsense-mediated mRNA decay switch exon in the ATM gene - Kralovicova, Jana, Moreno, Pedro M.D., Cross, Nicholas, Pego, Ana Paula and Vorechovsky, Igor Published:2016Publication:Nucleic Acid TherapeuticsVolume:26, (6)Page Range:392-400doi:10.1089/nat.2016.0635 Development and evaluation of a secondary reference panel for BCR-ABL1 quantitation on the International Scale - Cross, N.C.P., White, H.E. , Ernst, T., Welden, L., Dietz, C., Saglio, Guseppe, Mahon, F-X., Wong, C.C., Zheng, D., Wong, S., Wang, S-S., Akiki, S., Albano, F., Andrikovics, H., Anwar, J., Balatzenko, G., Bendit, I., Beveridge, J., Boeckx, N., Cerveira, N., Cheng, S-M., Colomer, D., Czurda, S., Daraio, F., Dulucq, S., Eggen, L., El Housni, H., Gerrard, G., Gniot, M., Izzo, B., Jacquin, D., Janssen, J.J.W.M., Jeromin, S., Jurcek, T., Kim, D-W., Machova-Polakova, K., Martinez-Lopez, J., McBean, M., Mesanovic, S., Mitterbauer-Hohendanner, G., Mobtaker, H., Mozziconacci, M-J., Pajič, T., Pallisgaard, N., Panagiotidis, P., Press, R.D., Qin, Y-Z., Radich, J., Sacha, T., Touloumenidou, T., Waits, P., Wilkinson, E., Zadro, R., Müller, M.C., Hochhaus, A. and Branford, S. Published:2016Publication:LeukemiaVolume:30, (9)Page Range:1844-1852doi:10.1038/leu.2016.90 Letter to the editor. Standardization of molecular monitoring for chronic myeloid leukemia in Latin America using locally produced secondary cellular calibrators - Ruiz, M.S., Medina, M., Tapia, I., Mordoh, J., Cross, N.C.P., Larripa, I. and Bianchini, M. Published:2016Publication:LeukemiaVolume:30Page Range:2258-2260doi:10.1038/leu.2016.197PMID:27451977