Haematological Cancer Genetics

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.

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

• Cancer Research UK
• Leukaemia and Lymphoma Research
• British Society for Haematology
• The Wellcome Trust

Collaborations

• Department of Haematology, University of Cambridge
• Centre for the study of Haematological Malignancies, Nicosia, Cyprus
• European Bioinformatics Institute

Selected Publications

• 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

  PUBMED: 23327922; DOI: 10.1182/blood-2012-07-446120

• 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

  PUBMED: 23478666; DOI: 10.1038/leu.2013.77

• 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

  PUBMED: 23477557; DOI: 10.1586/erm.13.1

• 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

  PUBMED: 23287868; DOI: 10.1182/blood-2012-07-441949

• 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

  PUBMED: 22968966; DOI: 10.1002/cyto.a.22116

• 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

  PUBMED: 21441929; PMC: 3084174; DOI: 10.1038/ng.796

• 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

  PUBMED: 20947725; DOI: 10.1126/science.1193004

• 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

  PUBMED: 20699138; DOI: 10.1016/S0076-6879(10)77006-3

• 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

  PUBMED: 19726804; PMC: 2737055; DOI: 10.1242/dmm.001644

• 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

  PUBMED: 16885051

• 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

  PUBMED: 16325696; DOI: 10.1016/S0140-6736(05)67785-9

• 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

  PUBMED: 16081246; DOI: 10.1016/j.ygeno.2005.06.012

• 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

  PUBMED: 15781101; DOI: 10.1016/S0140-6736(05)71142-9

• 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

  PUBMED: 15123827; PMC: 409920; DOI: 10.1073/pnas.0308195101