Cancer and Haematology

2004-2005

From left: Nick Nicola (Division Head), Warren Alexander, Doug Hilton, Ben Kile, Don Metcalf, Lorraine Robb, Andrew Roberts, Tim Thomas & Anne Voss.

• Research Focus
• Overview
• Email the Cancer & Haematology Division

Research Focus

• Genetic dissection of blood cell production and function
• Regulation of cytokine action
• Transcription factors and development

Overview

The Division’s focus is to understand at a molecular level the processes governing the production of white blood cells in health and disease. White blood cells provide the body’s defence system against infection. In situations where the numbers of white cells are reduced, such as during chemotherapy for cancer treatment or disease-related immunodeficiency, the risk of severe infection or bleeding is enhanced. Conversely, when the production of white blood cells occurs unchecked, or results in overactive cells, diseases such as leukaemia or autoimmunity can arise.

Our focus over many years has been blood cell hormones, or cytokines, that are vital to ensure that appropriate numbers of cells circulate in the blood as well as regulating their infection-fighting actions. Our original discovery of cytokines such as G-CSF and GM-CSF has led to the clinical use of these proteins to help patients receiving chemotherapy. Our research on the specific receptors for cytokines, which coordinate signals from the cell surface to the nucleus, which in turn instruct blood cells in their responses to cytokines, has led to valuable commercial collaborations to develop receptors as targets for discovery of new drugs for use in autoimmune diseases. More recently, our discovery of a new family of proteins that attenuates the intracellular signalling pathways triggered by cytokines, the suppressors of cytokine signalling (SOCS) proteins, has highlighted the regulation employed by the body that allows white blood cells to effectively destroy infectious invaders without collateral damage to tissues and organs.

Recently we have taken advantage of advances in mouse genomics to develop a program of gene discovery using genome-wide mutagenesis screens in mice. Initially focussing on blood platelets, which are essential to prevent excessive bleeding, 8 independent mutations have been isolated that can cure congenital platelet deficiency in mice, 3 of which involve the c-Myb/p300 transcription factor complex. Other such mutants highlight the importance of carbohydrate-modifying enzymes and thrombopoietin regulation in platelet production. In other screens, the isolation of mutant pedigrees with deficiencies in multiple blood cell lineages may reveal regulators of haemopoietic stem cells. The novel mutations emerging from these screens should continue to provide new insights into blood cell production as well as entry points to improved therapies for diseases of the blood-forming system.