Haemato-Oncology Unit

The Haemato-Oncology Unit is an integrated Unit that brings together basic laboratory research, molecular diagnostics and treatment of the blood cell cancers of adults and children (acute and chronic leukaemias, lymphomas and myeloma). The Unit’s major objectives are:

• To uncover the molecular mechanisms underlying the pathogenesis of leukaemias, lymphomas and myeloma (such as the blood cell cancers).
  
• To apply this knowledge to achieve two practical goals: (a) to advance our understanding of the aetiology of leukaemia leading in the long term to the introduction of preventive measures and (b) to improve the management of patients via the development of new molecular tools for differential diagnosis, prognosis, monitoring and treatment

Scientific Overview

Recent Highlights

• The identification (in collaboration with Professor Tariq Enver’s team in Oxford) of pre-leukaemic and leukaemic stem cells (LSC) for childhood leukaemia
• The finding that pre-leukaemic stem cells, driven by TEL-AML1 gain proliferative advantage in the presence of TGF beta
• Molecular dissection of the critical components for AML1-ETO mediated transformation
• Identification of an essential function of catalytic SET domain of NSD1 for Nup98-NSD1 mediated transformation
• Demonstration that loss of RARA expression in AML patient samples is connected with aberrant histone modification
• Characterisation of the interaction between PLZF and Rb, showing functional co-operation between the two proteins in transcriptional regulation of target genes

Future Aims

• To generate global genomic (SNP array-based) data supporting our infection model for childhood leukaemia
• To model in vitro and in vivo the transition of pre-LSC to LSC driven by TEL-AML1 gene fusion
• To document the timing of secondary genetic events (gene deletions) in childhood leukaemia
• To identify in more detail the mechanism of transcriptional repression by fusion genes and the involvement of key downstream target genes in paediatric and adult leukaemia
• To explore the roles and the potential therapeutic values of histone methylases and demethylases in oncogenesis
• To evaluate the role of histone deacetylases (particularly HDAC9) in non-Hodgkin’s lymphoma, in particular in the genomal centre lymphomas, and to validate HDAC9 as a therapeutic target
• To further identify global genetic profiles in myeloma that help define subtypes of disease and treatment response

Haemato-Oncology Clinical Unit - Royal Marsden Hospital

Head of Unit: Professor Gareth Morgan PhD FRCP FRCPath

• We aim to understand the genetic basis of the leukaemias, lymphoma and myeloma. The basic goal of this work is to develop predictive and prognostic biomarkers that can tell us how patients respond to treatment as well as allowing us to develop novel treatments targeting these molecules.

The Relevance to NHS Research and Development Programme

The work is relevant to the NHS Research & Development programme as we function as a Centre of Excellence for the use of conventional chemotherapy and stem cell transplantation for the management of the blood cell cancers. Within this treatment framework, we will introduce novel targeted therapies. In addition, we will use biological material derived from patients to understand the mechanisms underlying transformation of normal blood cells to their cancerous counterparts.

To evaluate new treatments we carry out clinical trials of new molecules looking at both their safety and their efficacy across the spectrum of blood cell cancers. We also have a large bone marrow transplant programme using both donor and autologous stem cells. The manipulation of the graft is an important scientific and clinical aim for which we have developed a specific relationship with the Anthony Nolan Fund.

Highlights

• Identified CYLD as a crucial tumour suppressor gene in the pathogenesis of myeloma
• Identified novel regions of genetic loss characteristic of different clinical outcomes in myeloma using SNP based gene mapping
• Identified MMSET as a crucial oncogene in myeloma as well as giving insight into its mechanism of action
• Published CLL4 study trial comparing standard versus fludarabine based treatment
• Finished Myeloma IX study, the largest myeloma trial ever carried out
• Mapped deletions at site of breakpoints in t(4;14) myeloma identifying potential new oncogenes
• Identified the role of copy number variation in genetic predisposition to myeloma
• Identified aminopeptidase inhibitors (chroma 2797) as being a novel and highly active new therapy for AML
• Identified genes and variants associated with thalidomide associated venous thrombotic events
• Identified CDKN2C as being a crucial tumour suppressor gene in myeloma
• Carried out cord blood transplants in adults with acute and chronic leukaemia
• Identified the poor prognosis associated with 17p- and p53 mutation in CLL
• Characterised factors associated with haemolysis in CLL
• Developed new combination chemotherapies based on thalidomide proteosome inhibitor drugs

Future direction

• Develop combination therapies with aminopeptidase inhibitors
• Develop kinase inhibitor affecting IRE1a
• To develop MMSET inhibitors targeting its HMT activity
• Characterised the methylation signatures characteristic of normal and malignant plasma cells
• Complete a global assessment of homozygous deletions and the genes within them which are typical of malignant plasma cells
• Complete an analysis of the impact of thalidomide in induction and maintenance on the response, PFS and OS of patients with myeloma in the MRC IX study
• Develop gene expression signatures characteristic of different outcomes for patients treated with thalidomide
• Characterise prognostic impact of genetic factors and outcome on myeloma
• Develop predictors of neuropathy in thalidomide treated patients
• Define inherited genetic characteristics defining patients at risk of developing myeloma
• Characterise biology of Hairy Cell Leukaemia and its variants
• Characterise role of HSP90 inhibitors in haematological malignancies