Haematological Cancer Genetics

The Haematological Cancer Genetics team, headed by George Vassiliou, studies the genes and genetic pathways involved in the development of these cancers, with a particular emphasis on Acute Myeloid Leukaemia and Multiple Myeloma. The ultimate goal of the team is to help develop treatments that can improve the survival and quality of life of cancer sufferers.

[Genome Research Limited]

Background

Blood cancers affect people of all ages worldwide. In recent years, our understanding of these cancers has improved dramatically as a result of advances made through scientific research. For some of the blood cancers, these advances have led to significant improvements in the survival and quality of life of sufferers. However, most blood cancers remain incurable and a lot more needs to be done before we are able to touch the lives of most patients. Our laboratory applies a number of approaches to facilitate this goal, focusing particularly on Acute Myeloid Leukaemia and Multiple Myeloma.

Acute myeloid leukaemia blasts in the blood of a mouse carrying the Npm1c mutation.

Acute myeloid leukaemia blasts in the blood of a mouse carrying the Npm1c mutation.

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Research

We study the pathogenesis of haematological cancers using both in vitro approaches and in vivo models designed to closely mimic the human diseases, in order to assist in the development of targeted treatments. Recently we developed a mouse model of the commonest form of human Acute Myeloid Leukaemia (NPM1c +ve) and identified, using transposon-based insertional mutagenesis, molecular pathways that collaborate with NPM1 mutations to promote leukaemogenesis. We are currently testing therapeutic approaches against AML using these findings. Additionally, we are applying a similar transposon-based approach to identify molecular pathways involved in the pathogenesis of Multiple Myeloma in the presence and absence of Myc overexpression.

Finally, in collaboration with other scientists and doctors at the Sanger Institute, the European Bioinformatics Institute and the University of Cambridge, we are developing molecular and computational tools to help us understand the clonal evolution of leukaemias arising through insertional mutagenesis and to accelerate the process of incorporating scientific findings into clinical diagnosis and decision-making.

Funding

Selected Publications

  • Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer.

    Ju YS, Alexandrov LB, Gerstung M, Martincorena I, Nik-Zainal S, Ramakrishna M, Davies HR, Papaemmanuil E, Gundem G, Shlien A, Bolli N, Behjati S, Tarpey PS, Nangalia J, Massie CE, Butler AP, Teague JW, Vassiliou GS, Green AR, Du MQ, Unnikrishnan A, Pimanda JE, Teh BT, Munshi N, Greaves M, Vyas P, El-Naggar AK, Santarius T, Collins VP, Grundy R, Taylor JA, Hayes DN, Malkin D, ICGC Breast Cancer Group, ICGC Chronic Myeloid Disorders Group, ICGC Prostate Cancer Group, Foster CS, Warren AY, Whitaker HC, Brewer D, Eeles R, Cooper C, Neal D, Visakorpi T, Isaacs WB, Bova GS, Flanagan AM, Futreal PA, Lynch AG, Chinnery PF, McDermott U, Stratton MR and Campbell PJ

    eLife 2014;3

  • Mouse models of NPM1-mutated acute myeloid leukemia: biological and clinical implications.

    Sportoletti P, Varasano E, Rossi R, Mupo A, Tiacci E, Vassiliou G, Martelli MP and Falini B

    Leukemia 2014

  • Capturing needles in haystacks: a comparison of B-cell receptor sequencing methods.

    Bashford-Rogers RJ, Palser AL, Idris SF, Carter L, Epstein M, Callard RE, Douek DC, Vassiliou GS, Follows GA, Hubank M and Kellam P

    BMC immunology 2014;15;1;29

  • Acute myeloid leukaemia: a paradigm for the clonal evolution of cancer?

    Grove CS and Vassiliou GS

    Disease models & mechanisms 2014;7;8;941-51

  • Vitamin B₁₂-dependent taurine synthesis regulates growth and bone mass.

    Roman-Garcia P, Quiros-Gonzalez I, Mottram L, Lieben L, Sharan K, Wangwiwatsin A, Tubio J, Lewis K, Wilkinson D, Santhanam B, Sarper N, Clare S, Vassiliou GS, Velagapudi VR, Dougan G and Yadav VK

    The Journal of clinical investigation 2014;124;7;2988-3002

  • Calreticulin gene exon 9 frameshift mutations in patients with thrombocytosis.

    Chi J, Nicolaou KA, Nicolaidou V, Koumas L, Mitsidou A, Pierides C, Manoloukos M, Barbouti K, Melanthiou F, Prokopiou C, Vassiliou GS and Costeas P

    Leukemia 2014;28;5;1152-4

  • Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia.

    Dawson MA, Gudgin EJ, Horton SJ, Giotopoulos G, Meduri E, Robson S, Cannizzaro E, Osaki H, Wiese M, Putwain S, Fong CY, Grove C, Craig J, Dittmann A, Lugo D, Jeffrey P, Drewes G, Lee K, Bullinger L, Prinjha RK, Kouzarides T, Vassiliou GS and Huntly BJ

    Leukemia 2014;28;2;311-20

  • Network properties derived from deep sequencing of human B-cell receptor repertoires delineate B-cell populations.

    Bashford-Rogers RJ, Palser AL, Huntly BJ, Rance R, Vassiliou GS, Follows GA and Kellam P

    Genome research 2013;23;11;1874-84

  • A powerful molecular synergy between mutant Nucleophosmin and Flt3-ITD drives acute myeloid leukemia in mice.

    Mupo A, Celani L, Dovey O, Cooper JL, Grove C, Rad R, Sportoletti P, Falini B, Bradley A and Vassiliou GS

    Leukemia 2013;27;9;1917-20

  • Detailed molecular characterisation of acute myeloid leukaemia with a normal karyotype using targeted DNA capture.

    Conte N, Varela I, Grove C, Manes N, Yusa K, Moreno T, Segonds-Pichon A, Bench A, Gudgin E, Herman B, Bolli N, Ellis P, Haddad D, Costeas P, Rad R, Scott M, Huntly B, Bradley A and Vassiliou GS

    Leukemia 2013;27;9;1820-5

  • A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention.

    Rad R, Cadiñanos J, Rad L, Varela I, Strong A, Kriegl L, Constantino-Casas F, Eser S, Hieber M, Seidler B, Price S, Fraga MF, Calvanese V, Hoffman G, Ponstingl H, Schneider G, Yusa K, Grove C, Schmid RM, Wang W, Vassiliou G, Kirchner T, McDermott U, Liu P, Saur D and Bradley A

    Cancer cell 2013;24;1;15-29

  • Activity of a heptad of transcription factors is associated with stem cell programs and clinical outcome in acute myeloid leukemia.

    Diffner E, Beck D, Gudgin E, Thoms JA, Knezevic K, Pridans C, Foster S, Goode D, Lim WK, Boelen L, Metzeler KH, Micklem G, Bohlander SK, Buske C, Burnett A, Ottersbach K, Vassiliou GS, Olivier J, Wong JW, Göttgens B, Huntly BJ and Pimanda JE

    Blood 2013;121;12;2289-300

  • The role of high-throughput technologies in clinical cancer genomics.

    Idris SF, Ahmad SS, Scott MA, Vassiliou GS and Hadfield J

    Expert review of molecular diagnostics 2013;13;2;167-81

  • Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice.

    Dovey OM, Foster CT, Conte N, Edwards SA, Edwards JM, Singh R, Vassiliou G, Bradley A and Cowley SM

    Blood 2013;121;8;1335-44

  • Detection of cytoplasmic nucleophosmin expression by imaging flow cytometry.

    Grimwade L, Gudgin E, Bloxham D, Bottley G, Vassiliou G, Huntly B, Scott MA and Erber WN

    Cytometry. Part A : the journal of the International Society for Analytical Cytology 2012;81;10;896-900

  • Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice.

    Vassiliou GS, Cooper JL, Rad R, Li J, Rice S, Uren A, Rad L, Ellis P, Andrews R, Banerjee R, Grove C, Wang W, Liu P, Wright P, Arends M and Bradley A

    Nature genetics 2011;43;5;470-5

  • PiggyBac transposon mutagenesis: a tool for cancer gene discovery in mice.

    Rad R, Rad L, Wang W, Cadinanos J, Vassiliou G, Rice S, Campos LS, Yusa K, Banerjee R, Li MA, de la Rosa J, Strong A, Lu D, Ellis P, Conte N, Yang FT, Liu P and Bradley A

    Science (New York, N.Y.) 2010;330;6007;1104-7

  • The use of DNA transposons for cancer gene discovery in mice.

    Vassiliou G, Rad R and Bradley A

    Methods in enzymology 2010;477;91-106

  • New approaches for modelling sporadic genetic disease in the mouse.

    Fisher EM, Lana-Elola E, Watson SD, Vassiliou G and Tybulewicz VL

    Disease models & mechanisms 2009;2;9-10;446-53

  • An acquired translocation in JAK2 Val617Phe-negative essential thrombocythemia associated with autosomal spread of X-inactivation.

    Vassiliou GS, Campbell PJ, Li J, Roberts I, Swanton S, Huntly BJ, Fourouclas N, Baxter EJ, Munro LR, Culligan DA, Scott LM and Green AR

    Haematologica 2006;91;8;1100-4

  • Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study.

    Campbell PJ, Scott LM, Buck G, Wheatley K, East CL, Marsden JT, Duffy A, Boyd EM, Bench AJ, Scott MA, Vassiliou GS, Milligan DW, Smith SR, Erber WN, Bareford D, Wilkins BS, Reilly JT, Harrison CN, Green AR, United Kingdom Myeloproliferative Disorders Study Group, Medical Research Council Adult Leukaemia Working Party and Australasian Leukaemia and Lymphoma Group

    Lancet 2005;366;9501;1945-53

  • L3mbtl, the mouse orthologue of the imprinted L3MBTL, displays a complex pattern of alternative splicing and escapes genomic imprinting.

    Li J, Bench AJ, Piltz S, Vassiliou G, Baxter EJ, Ferguson-Smith AC and Green AR

    Genomics 2005;86;4;489-94

  • Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.

    Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR and Cancer Genome Project

    Lancet 2005;365;9464;1054-61

  • Imprinting of the human L3MBTL gene, a polycomb family member located in a region of chromosome 20 deleted in human myeloid malignancies.

    Li J, Bench AJ, Vassiliou GS, Fourouclas N, Ferguson-Smith AC and Green AR

    Proceedings of the National Academy of Sciences of the United States of America 2004;101;19;7341-6

* quick link - http://q.sanger.ac.uk/appstgen