Title: Investigating the mechanisms of relapse in Juvenile Myelomonocytic Leukaemia (JMML)
Funder: The Academy of Medical Sciences

Abstract: Aims: 1. To investigate the immunometabolomic landscape of the JMML LSC, with a particular focus in mechanisms that negatively regulate tumour clearance and promote LSCs survival. 2.To investigate the therapeutic vulnerabilities of the pathways identified above validate the effect of already available immune-checkpoint inhibitors in JMML alone / in combination with the pharmacological inhibition of metabolic pathways in vitro and in vivo. JMML is an extremely rare and aggressive childhood leukaemia that currently has no curative treatments available other than Bone Marrow Transplantation (BMT). Despite this being a very radical therapy, treatment failure due to high relapse rates occurs in 35% of patients. Therefore JMML specific targeted treatments are urgently required in order to alter the poor prognosis for this disease. My recent work on JMML has lead to the identification of the JMML cell of origin (JMML LSC) which is key to developing new disease specific therapies . Through computational analysis of transcriptomic data from patient samples at diagnosis, I began to unravel the JMML LSC therapeutic vulnerabilities. Preliminary analysis from the project to date has demonstrated that genes involved in metabolic pathways and negative regulators of regulatory T-cells are particularly enhanced in the relapse patient cohort. This research project aims to investigate the mechanism of disease relapse by performing a combined analysis of the JMML LSC immunometabolomic signature using serial samples from diagnosis, post-BMT and at relapse in order to study the dynamics of disease relapse and identify novel therapeutic targets that hopefully alter the disease poor prognosis.

Lay abstract: Juvenille Myelomonocytic Leukaemia ( JMML) is an extremely rare leukaemia that constitutes 1-2% of childhood leukaemias; which currently does not have good treatment options as drugs frequently used in acute leukaemias do not show any benefit in JMML. This leads to poor disease survival as JMML frequently comes back even after radical treatments such as Bone Marrow Transplantation. This indicates that we need to understand the JMML cells better in order to be able to kill the cancer cells effectively. My previous work has enable us to identify the JMML specific cells, called the JMML stem cells, that cause the disease to come back; and now I aim to study these cells in detail in order to identify the mechanisms that allow the JMML cells survive the current treatments. From the analysis we have done already on the JMML stem cells, we can see that they appear to have certain properties such as: 1. switching off the ability of our immune system to kill the cancer cells, 2. Being able to alter the metabolism of the cells possibly allows them to escape treatment. My work now will aim to understand how these properties develop and identify ways by which we can switch off this abnormal process by using drugs that can specifically kill the JMML cells. This should have huge benefits for the patients, as it will alter the disease prognosis and enable us to cure more children with JMML, which is currently not possible.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS