Cancer stem cells
Studying the characteristics of leukaemia cells to increase our understanding of the differences between stem cells that can initiate leukaemia and haemopoietic stem cells that produce normal blood cells.
Directed by , Principal Clinical Scientist, the group is primarily focused on investigating childhood leukaemia. By studying the characteristics of leukaemia cells we are seeking to increase our understanding of the differences between stem cells that can initiate leukaemia and haemopoietic stem cells that produce normal blood cells.
Acute lymphoblastic leukaemia (ALL) is the most common paediatric cancer with survival rates of 80-85%. However, a significant proportion of patients relapse (≈20-25%). Around half of acute leukaemia cases that relapse undergo more intensive therapy involving stem cell transplantation. NHS Blood and Transplant laboratories perform over 3000 procedures for transplant patients annually. The high relapse rate emphasises the need for more effective therapy, which may improve survival rates and quality of life for patients. Understanding the characteristics of leukaemia stem cells will assist the development of therapeutic strategies specifically targeting these cells and permit refinement of disease monitoring throughout the course of treatment.
Characterisation of leukaemia initiating cell populations in childhood leukaemias
While chemotherapy can cure most cases of childhood leukaemias, a proportion of patients relapse because the leukaemia cells have not been destroyed. It is not known why some patients fail to respond to drug treatments but one thought is that some drugs may not attack a particular group of cells, known as leukaemia stem cells. Leukaemia stem cells can duplicate themselves generating new leukaemia cells and could be responsible for relapse of the disease. We have identified cells that have properties of leukaemia stem cells and are investigating the effectiveness of cancer drugs on these cells. We have demonstrated these leukaemia cells have cell surface markers that are similar to normal haemopoietic stem cells and they are less affected by therapeutic drugs. Therefore, these drug resistant stem cells may be responsible for relapse. We plan to further characterise these leukaemia stem cells to help us understand their mechanisms of resistance and to assist in the development of new therapeutic strategies.
Development of new therapeutic strategies targeted at leukaemia initiating cells and improvement of disease monitoring
We are investigating the effects of current and novel therapeutic agents on leukaemia stem cells and comparing their responses with normal haemopoietic cells. With funding from the National Institute for Health Research we will also investigate whether the leukaemia stem cells express similar gene rearrangements to those identified at diagnosis, that are used to track levels of residual disease. Clinical response to therapy, measured by examining these patient specific gene rearrangement markers, is a good indicator of relapse risk. However, in some patients the profile of rearrangements detected at relapse differs from that observed at diagnosis. When a new marker appears at relapse it is not clear whether it represents emergence of a new malignant clone or whether it represents subpopulations that were present only at very low levels at diagnosis and undetectable by routine screening. We will use this approach to investigate whether leukaemia initiating cells have similar gene rearrangements to those identified at diagnosis or whether these cells harbour unique rearrangements that may become predominant clones at relapse. The findings could result in improvements in disease monitoring throughout treatment.
Ex-vivo expansion of haemopoietic cells to produce therapeutic quantities of committed progenitor cells in culture
Many cancer patients treated with high dose chemotherapy, prior to haemopoietic stem cell transplantation (HSCT), develop profound thrombocytopenia and are at increased risk of developing severe bleeding complications. However, the recurrent platelet transfusions used to alleviate these complications carry the risk of infection and alloimmunisation. Reinfusion of ex vivo expanded megakaryocyte and granulocyte progenitor cells together with the HSCT may enhance platelet and neutrophil recovery in these patients. The emergence of vCJD as a possible transfusion risk has focussed attention on the need to explore alternative sources of blood products. The purpose of this project is to develop ex-vivo culture conditions for haemopoietic progenitor cells.
Cultured leukaemia cell demonstrating presence of the ETV6-RUNX1 fusion, present in ≈25% of childhood leukaemias
Confocal image of leukaemia cells demonstrating expression of transcription factor NF-κB