Title: Microenvironmental metabolic regulation in myeloid malignancies - Studentship
Funder: Cancer Research UK

Abstract: Microenvironmental metabolic regulation in myeloid malignancies Background Myeloid malignancies are caused by genetic or epigenetic alterations in haematopoietic stem cells (HSCs) and/or myeloid progenitor cells (MPCs). They comprise myeloproliferative neoplasms (MPNs), myelodysplastic syndromes and acute myeloid leukaemia (AML). MPN (and particularly myelofibrosis) patients have higher risk of AML. Different molecular alterations in AML might require specific treatments. However, most selective inhibitors also affect normal haematopoiesis, and clones carrying other mutations can cause relapse after chemotherapy. Therefore, overcoming common mechanisms mediating leukaemic survival and/or resistance might improve current treatments. HSCs/MPCs can transform into chemoresistant leukaemic stem cells (LSCs) that cause tumour relapse. Increasing evidence support a key role of the microenvironment or “niche” where LSCs reside during leukaemogenesis and resistance. Our past work identified bone marrow mesenchymal stem cells (BMSCs) with essential HSC niche functions. We showed that extrinsic regulation of HSCs by the autonomic nervous system or by hormones like oestrogens might have therapeutic effects in MPN –currently being tested in two Phase-II multicentre clinical studies. Data from others and our group suggest that the microenvironment is progressively hijacked during leukaemogenesis, becoming poorly supportive towards normal haematopoiesis, but instead nurturing and chemoprotective for LSCs. Aims The overall goal is to decipher key microenvironmental changes contributing to leukaemogenesis. The driving hypothesis is: resembling the accrual in haematopoietic cells of highly recurrent mutations that initiate leukaemia, key stepwise alterations of the microenvironment also contribute to leukaemogenesis. We hypothesise that these are triggered by inflammation, hypoxia and energy demand and favour a) clonal selection, leading to the expansion of dominating clones; b) the transition from indolent preleukaemia to myelofibrosis or leukaemia and c) chemoresistance. We will focus on candidate mechanisms potentially involved in A) expansion of preleukaemic cells in specific niches, B) microenvironment remodelling leading to permissive niches where myelofibrosis or leukaemia develop and C) the metabolic adaptation of the microenvironment that favours leukaemia survival and chemoresistance. Methods Both basic (mouse) and translational (patient-to-bench research tagged to ongoing clinical studies) multidisciplinary research based on analysis of human samples, genetically-modified mice, RNAseq, CHIPseq, MS, Metabolomics, intravital microscopy, novel co-culture systems, inhibitors and CRISPR/cas9 genomic editing. Samples from AML and MPN patients and xenograft models will be analysed to establish the clinical relevance of these findings. Results The results of this project will unravel microenvironmental changes underlying the evolution, survival and resistance of myeloid malignancies, potentially leading to novel, more efficient combination therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS