Gut-immune-leukaemia crosstalk in aged AML: mechanisms of response to p38 MAPK-targeted combination therapy
Closing date: 23/11/2026
Clinical Research Training Fellowship: Gut-immune-leukaemia crosstalk in aged AML: mechanisms of response to p38 MAPK-targeted combination therapy
Lead Supervisors: Dr Simona Valletta
Co-Supervisors: Professor Amaya Viros, Dr Justin Loke, Dr Evangelos Giampazolias
Applications Deadline: 12:00pm Monday 23rd November 2026
Interviews: Friday 5th February 2027 (in Manchester)
Start date: September 2027
Project Keywords: Acute Myeloid Leukaemia, Tumour Immunology, Gut Microbiome
Research Opportunity: Clinical Research Training Fellowship leading to the award of PhD
Project Outline
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.
Applications for this project are now open. Please complete your application on The University of Manchester website.
About Dr Simona Valetta (project Lead Supervisor)
“I am a Group Leader at the University of Manchester, where I lead the Leukaemic Stem Cell Niche Group. My research focuses on understanding how leukaemic cells interact with the bone marrow microenvironment in acute myeloid leukaemia (AML), with a particular interest in how ageing influences the development and progression of leukaemia. Our research aims to better understand the biology of leukaemia and identify new therapeutic approaches.
I am an active member of the European Hematology Association (EHA) and a member of the EHA’s Specialized Working Groups on Stem Cells, AML, and Aging in Hematology. I also sit on the Blood Cancer UK Fellowship Committee and Leukaemia UK John Goldman Fellowship Committee and contribute to the organisation of international scientific meetings.
I welcome applications from motivated PhD candidates interested in combining clinical insight with laboratory research to address important questions in AML, ageing and leukaemia biology, with the potential to translate research findings into improved patient care.”
Key information
Before submitting an application, please ensure you have read the information below about the funding arrangements and eligibility for our Clinical Research Training Fellowships.
We also encourage you to get in contact with the lead supervisor to discuss the project and any particulars.
Further information is available on the Clinical Research Training Fellowships webpage.
The clinical fellowships are usually tenable for three years, although in certain circumstances they may be four years duration. The Fellowship covers:
- running expenses,
- an appropriate salary in line with the applicant’s current NHS salary and grade
- full coverage of University PhD fees at the UK/home fee rate.
International Candidates
The University of Manchester aims to support the most outstanding applicants from outside the UK.
We are able to offer a limited number of bursaries to high-performing EU and international candidates, covering PhD fees only. Bursaries do not include financial support for visa/health surcharges.
We assess each EU and international candidate’s suitability for a bursary at the application and interview stages.
You must be a post-registration clinician, and ideally have a specialist post in a related subject, to apply for our Clinical Research Training Fellowships.
Applicants must hold an MBChB degree or an equivalent medical qualification. You should also hold, or be about to obtain, a minimum upper second class (or equivalent) undergraduate degree in a relevant subject. A related master’s degree would be an advantage.
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.
Applications for this programme are now open. Please submit your application on The University of Manchester application portal.
Key dates
- Applications open: Monday 5th October 2026
- Application deadline (all projects): 12:00pm Monday 23rd November 2026
- Clinical Interviews: Friday 5th of February 2027 (in Manchester)
- Start date: September 2027 with flexible starts for clinicians
Useful Links
Submit your application
Interested in applying for this opportunity? Submit your application on The University of Manchester application portal.
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