2015 JOHN GOLDMAN FELLOWS
FOR FUTURE SCIENCE
Dr Salima (Sarah) Nurmohamed, University of Oxford
Characterisation of GATA2 in blood development and leukaemia
Acute myeloid leukaemia (AML) is the most common type of blood cancer in adults. AML is highly malignant and most patients eventually die from the disease despite aggressive therapy. A key challenge in determining how blood cell fate is altered to cause leukaemia, is to understand the way that errors in the DNA-code adversely affect the expression of genetic information. The GATA2 protein is a master-regulator of blood cell development with two main functions – it binds DNA to switch genes on or off and can simultaneously associate with other proteins to regulate gene expression. Interruption of these interactions alters blood cell development. Despite the identification of many GATA2 mutations in AML patients, the mechanism of how these errors cause leukaemia remains unknown. Adopting a multidisciplinary approach, this work aims to decipher the molecular mechanism of GATA2 in normal blood development and elucidate how GATA2 mutations cause AML. Results from this work endeavour to drive the design and development of novel therapies.
Dr Elspeth Payne, Cancer Institute, University of Central London
Using in vivo small molecule screens to develop novel therapeutics for MDS5q
Myelodysplastic syndrome (MDS) is a haematological malignancy with a predisposition to evolution to acute myeloid leukaemia (AML). A subtype of MDS is characterised by recurrent loss of the long arm of chromosome 5 (MDS5q). Recent studies suggest that loss of 5q is the initiating lesion in these MDS patients and that the gene responsible for the dominant phenotype in patients (anaemia) is ribosomal protein of the small subunit 14 (RPS14) located in the critically deleted region of 5q. We have developed a model for MDS5q using zebrafish and conducted an in vivo small molecule screen using zebrafish fry. We have identified potential novel therapeutics using this strategy. This project with extend our validation of screen hits and increase the breadth of compounds screened with the goal of developing new therapeutics for MDS patients.
Myelodysplastic syndrome (MDS) is a blood cancer that usually begins with symptoms from anaemia (low numbers of red blood cells). This can progress over time to a more severe illness and eventually leukaemia. Most patients with MDS die from leukaemia or infections as a result of the disease. The only curative treatment for MDS is a bone marrow transplant. Bone marrow transplants require a suitable donor and are often associated with severe side effects. This makes bone marrow transplants unsuitable treatments for many patients. This research aims to uncover new treatments that will be effective at improving symptoms and prolonging survival, with the ultimate goal of curing patients with MDS.
Dr G Vignir Helgason, Wolfson Wohl Cancer Research Centre, University of Glasgow
Autophagy-Dependent Regulation of Energy Metabolism in Leukaemic Stem Cells
Cancer cells require to make metabolic and mitochondrial changes to fuel their high energy demands. Therefore, targeting metabolic reprogramming is predicted to offer novel opportunities for cancer treatment. We have preliminary data suggesting that i) BCR-ABL drives an increase in cellular metabolic capabilities in primary chronic myeloid leukaemia (CML) progenitor cells and ii) autophagy, a catabolic process that leads to degradation of mitochondria, is an important regulator of metabolism in CML. This has encouraged us to extend our investigations in more primitive CML leukaemic stem cells (LSCs) which represent the reservoir of cancer cells that needs to be eradicated in order to cure patients. We have already developed improved protocols for metabolic assays in rare LSCs and aim in this proposal to reveal important vulnerabilities in CML LSCs that can be targeted therapeutically in future clinical trials and have broader application to other stem cells driven leukaemias.
The identification of LSCs in the late 1990s advocated the idea that leukaemia is primarily driven by a rare population of cancer stem cells. This has important clinical implications since many anti-leukaemia therapies are evaluated based on their ability to reduce leukaemia burden, but if the therapies are not killing the LSCs, the leukaemic cells may develop drug resistance with time, causing disease relapse and death. CML patients are currently treated with drugs called tyrosine kinase inhibitors (TKIs), which inhibit the function of the onco-protein BCR-ABL; however we have recently shown that CML LSCs can survive TKI treatment indicating that TKI mono-therapy will not lead to cure and combination therapy is therefore required to cure CML patients. In this proposal we plan to investigate vulnerabilities in energy metabolism in CML LSCs and use the best pre-clinical models available for CML to identify novel drug targets for CML LSC eradication.
Dr Lisa J Russell, Northern Institute for Cancer Research, Newcastle University
Characterisation of a novel gene fusion in acute lymphoblastic leukaemia
Chromosomal abnormalities are a characteristic trait of cancer cells. Their identification has led to improvements in diagnosis and outcome in leukaemia, in particular acute lymphoblastic leukaemia (ALL). The deregulated expression of the type I cytokine receptor, CRLF2, identified that tyrosine kinase inhibitors could be clinically relevant. Study of the genomes of patients with deregulated expression of CRLF2 (CRLF2-d) identified additional aberrations: one is unique to CRLF2-d patients. Paired-end sequencing and SNP arrays identified the novel fusion of a deubiquitinase gene to a RNA helicase gene. This fusion is expressed and appears to remove the ubiquitin carboxyl-terminal hydrolase domain of the deubiquitinase, likely resulting in loss of function, allowing proteins that would otherwise be degraded, to prevail in the cell, contributing to leukaemic development. This project aims to characterise this fusion by investigating the expression levels of these genes, creating assays for rapid detection relevant both clinically and to ascertain an accurate incidence and prognostic value. Cellular manipulations including knockdown and expression will evaluate the effects on proliferation, viability, death and cell cycle. RNA-sequencing will identify important downstream pathways deregulated by this fusion, which could provide a novel therapeutic target for treatment.
We have identified a new genetic abnormality present in patients with acute lymphoblastic leukaemia. Genetic material is lost between two genes on chromosome X, which leads to them becoming fused together. We plan to investigate the effects of this fusion event. We are interested in the expression levels of these genes and whether this is altered due to the fusion. We plan to design a simple test that could be used in the clinic to identify this fusion quickly and cost effectively. We also plan to create this fusion in human cells and investigate the effects on cell growth and death. We hope to identify important downstream pathways affected by this fusion, which could identify new targets, which lend themselves to therapeutic intervention.
Dr Fernando dos Anjos Afonso, European Cancer Stem Cell Research Institute, Cardiff
Exploring the roles of canonical and non-canonical Notch signalling to target human acute myeloid leukaemia
Hematopoietic stem/progenitor cells (HSPCs) and acute myeloid leukaemia-initiating cells (AML-ICs) share a number of biological features but there are also critical differences that can be exploited therapeutically. Notch signalling is critical in a number of stem cell systems but little is known on its function in AML. Recent evidences suggest that leukaemic cells have evolved mechanisms to evade Notch signals as an additional way to escape apoptosis. Understanding how this pathway is activated/controlled extrinsically in AML-ICs and how AML escapes Notch signals, could be used to develop new therapies. We will systematically investigate how AML evades apoptosis triggered by Notch signals (i), and by employing an in vitro niche-based model to establish first whether this could also be used as novel therapeutic target (ii).
Blood stem cells are responsible for the growth and maintenance of all mature cells in our blood. Most of the current treatments for one type of leukaemia, named acute myeloid leukaemia or AML, are very toxic and not very specific (targeting many cell- types including blood stem cells), hence many patients tolerate such treatments poorly. If we can better understand the differences between the blood stem cells and the cells that drive AML formation, we can exploit these differences therapeutically. Indeed, one of the mechanisms, the “Notch Pathway”, positively regulates blood stem cell maintenance but is detrimental for cells that drive AML formation. In this application we propose to understand first how AML avoids the Notch pathway as an alternative way to escape cell death. Hopefully we can target more specifically AML by understanding these mechanisms.