(MCRC Clinical) Gut-Immune-Leukaemia Crosstalk in Aged AML: Mechanisms of Response to p38 MAPK-Targeted Combination Therapy

About the project

About the Project Acute myeloid leukaemia (AML) predominantly affects older patients, who tolerate intensive curative therapy poorly and are typically treated with non-curative regimens involving azacitidine (AZA), alone or with the BCL-2 inhibitor venetoclax (VEN). Ageing is associated with immunosenescence, chronic low-grade inflammation ("inflammageing"), dysregulated p38 MAPK signalling and gut dysbiosis, all of which may shape leukaemogenesis and treatment response. Using a novel non-irradiated aged mouse model of MLL-AF9-rearranged AML that preserves host immune competence, we have shown that combining AZA with the novel p38 MAPK inhibitor POLB 001 (Poolbeg Pharma) markedly enhances CD8+ T-cell-mediated anti-leukaemic immunity, with increased Granzyme B production and reduced PD-1/LAG-3 exhaustion marker expression, compared with mice treated with AZA alone. Aim 1 will profile p38MAPK signalling, immune composition and inflammatory and gut microbiome signatures in primary bone marrow and plasma samples from AML patients over 65, using an optimised spectral flow cytometry panel, Luminex-based cytokine profiling and 16S rRNA/shotgun metagenomic sequencing. Patient-derived organoids incorporating immune and stromal components will be used to assess ex vivo cytotoxicity and metabolic responses to AZA, AZA/VEN and POLB 001-based combinations, with CODEX multiplexed imaging of matched trephines spatially mapping leukaemic, immune and stromal compartments. Aim 2 will characterise treatment-induced changes in gut microbiome composition, intestinal barrier integrity (FITC-dextran permeability) and mucosal/systemic inflammatory cytokines (IL-1α, IL-1β, IL-6, TNFα) in young versus aged mice receiving AZA, POLB 001 and VEN, alone or combined. Aim 3 will establish whether these microbiome changes affect leukaemia susceptibility. Faecal microbiota from treated or untreated aged mice (Aim 2) will be transplanted into antibiotic-depleted aged recipients, which will then be challenged with MLL-AF9 cells to assess effects on leukaemic engraftment. Together, these studies will define immune, inflammatory and microbiome-associated biomarkers of response and establish translational rationale for combining POLB 001 with standard-of-care therapy in older AML patients. Eligibility You must be a post-registration clinician and therefore must hold an MBChB degree or equivalent medical degree and ideally have a specialist post in a related subject, to apply for our Clinical Research Training Fellowships. It is generally expected that CRTFs will return to a training programme in the UK upon completion of their research degree. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English language) before contacting potential supervisors to express an interest in their project. Eligibility information can be found on the University's Country Specific information page. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply Apply directly via this link: https://tinyurl.com/577zjazd or on the online application portal, select MCRC PhD Programme as the programme of study. You may only apply for one project within this scheme. Please ensure that your application includes all required supporting documents: Curriculum Vitae (CV) Supporting Statement Academic Certificates and Transcripts Incomplete or late applications will not be considered. Further details are available on our website: CRUK Manchester Centre PhD Training Scheme | Biology, Medicine and Health | University of Manchester Application Timeline Applications open: Monday, 5 October 2026 Application deadline: Monday, 23 November 2026 Interview date: Week commencing 11 January 2027 Start date: September 2027 Equality, diversity and inclusion are central to the University’s activities. The full statement can be found here: https://www.bmh.manchester.ac.uk/study/research/getting-started/equality-diversity-inclusion/”

Research areas