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Juvenile myelomonocytic leukaemia (JMML) is a very rare type of slowly developing blood cancer that occurs in young children.
Characterisation of the cross talk between RAS mutant haematopoietic stem cells and immune effector cells in Juvenile Myelomonocytic Leukaemia
Professor Adam Mead
University of Oxford
Oxford, OX3 9DS
1 September 2023
36 months
£349,999.54
Juvenile myelomonocytic leukaemia (JMML) is a very rare type of slowly developing blood cancer that occurs in young children. JMML is an aggressive form of leukaemia for which there are limited treatment options as chemotherapy drugs used to treat other leukaemias do not show any benefit. Haematopoietic stem cell transplantation (HSCT) offers the only chance for cure in JMML; however, 40% do not respond and sadly in some cases are incurable.
In 2015 Professor Adam Mead and his team established a national JMML study, which identified the ‘source’ of cells causing disease relapse, called the JMML leukaemia stem cells (LSC). This initial work will now provide the stepping stone for the in-depth study of the leukaemia cells and which treatments are likely to eradicate such malignant (cancerous) populations. The team hypothesise that in some cases, the leukaemia stem cells are able to switch off the patient’s own immune cells, thereby preventing them from efficiently attacking leukaemia. If this is well understood this can identify ways by which the process can be blocked or reversed. The ultimate aim of this project is to identify ways to harness the patient’s own immune response to improve the outcome of patients with JMML.
Malignant leukaemia cells use certain mechanisms to interact with their environment in the bone marrow which aids their survival following treatment and contributes to relapse. The pathways by which the JMML LSC interact with the rest of the cells in the bone marrow has never been investigated to date, this information can help in the development of future therapies. Cytotoxic immune cells are the key mechanism that contributes to leukaemia eradication following stem cell transplantation, understanding the characterisation of the cross talk between the LSC and immune system is key to understanding why relapse occurs so often after stem cell transplantation in JMML and design of new treatment pathways. Professor Adam Mead aims to understand how the immune system interacts with the JMML LSC, and design therapies to reverse the pathways that cause relapse following stem cell transplantation.
Professor Mead and his team anticipate that this internationally unique dataset and bioinformatic pipelines will provide great insights to the mechanisms of relapse in JMML, and potentially other RAS-mutant associated myeloid disorders that fail to respond following stem cell transplantation. This has never been investigated in JMML and in other conditions such as AML, analysis is often limited at two time points at diagnosis and disease relapse.
This study provides a unique window in the early post HSCT period, and an opportunity to understand and characterise the haematopoiesis (the process by which blood cells are formed), during this time and the mechanisms that propagate immune escape.
The discovery of relapse associated disease specific markers will allow evidenced based risk stratification and future implementation of novel therapies to this high risk patient group. Following the completion of the work described in this project similar academic/NHS/industry partnerships will ensure rapid translation of discovery in academic laboratories and direct patient benefit. Any promising agents will be taken forward in international clinical trials through already established international networks and collaborations focusing on JMML and will also be supported by the UK JMML parent group.
Professor Adam J Mead is a Professor of Haematology at the University of Oxford whose overarching research focus is to characterise genetic and cellular heterogeneity in myeloproliferative neoplasms (MPN) and related myeloid neoplasms with the ultimate goal to improve the diagnosis, risk-stratification and treatment of these largely incurable forms of blood cancer.
Professor Mead is working with a highly skilled team including Prof Irene Roberts (Professor of Paediatric Haematology, University of Oxford), Dr Eleni Louka (NIHR Academic Clinical Lecturer in Paediatric Haematology, University of Oxford) and Dr Anupama Rao (Paediatric Haematology Consultant, Great Ormond Street Hospital).
The team to date has established a national multi-centred study, a unique patient samples biobank and performed initial work identifying which are the leukaemia propagating cells in JMML and lead to the discovery of CD96 as a novel cell-surface target. The team will collaborate with Prof Rachael Bashford-Rogers (Associate Professor of Molecular and Cellular Biochemistry, University of Oxford) and her insights into cancer immunology and understanding of how the immune system interacts with cancer cells.
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