4-year PhD Studentship: The bone marrow-derived stromal cells – a therapeutic target in haematological malignancy

Bone marrow consists of blood stem cells known as haematopoietic stem cells (HSC) embedded in a matrix of diverse cell populations referred to as the bone microenvironment or ‘niche’. Blood cancers including multiple myeloma, leukaemia and lymphoma arise from spontaneous, genetic abnormalities in blood cells derived from HSC and these cells have been the major focus of research to date. However, there is increasing recognition of the importance of the bone marrow microenvironment in supporting growth and maturation of HSC, and that dysregulation of this complex environment acts as a driver for haematological malignancy [1].

Within the multicellular environment of the bone marrow niche, mesenchymal stromal cells (MSC) are known to have a key role influencing HSC fate, particularly in ageing which is a risk factor for blood cancer [2].

Building on recent findings of distinct MSC subpopulations in leukaemia [3], altered MSC function in myelodysplastic syndromes [4,5] and new insights from multi-omic analyses [6] as well as the emergence of anti-stromal cell therapies currently under investigation in other cancers (most notably pancreatic carcinoma [7]), we will investigate MSC function with a view to identifying novel therapeutic interventions for haematological malignancies.

Aims and objectives

The overall aim of the studentship is to improve clinical outcomes for people with haematological malignancy via elucidation and subsequent manipulation of the role of MSC in initiation, progression and chemoresistance in haematological malignancies.

The objectives are:

i. To characterise MSC subpopulations in bone marrow samples from people with myelodysplastic syndromes, leukaemia and lymphoma

ii. To examine the effect of MSC isolated from people with haematological malignancies on ex vivo haematopoiesis

iii. To investigate the effects of known stromal cell modulators on haematopoiesis in vitro and, for selected agents of promise, in in vivo models of haematological malignancy.

Methodology

Diagnostic blood and bone marrow samples (aspirate and trephine) isolated from people with haematological malignancies will be analysed and MSC sub-populations characterised using FACS and (immuno)histochemistry.

Models of ex vivo haematopoiesis designed to mimic the bone marrow niche will incorporate patient-derived MSC and will be compared with age-matched MSC isolated from control subjects with analysis of HSC proliferation and differentiation. Known and emerging anti-stromal agents will be added to the models and their effects on haematopoiesis examined.

The student can expect to become proficient in bone marrow histopathology, isolation and culture of primary human cells, FACS, ELISA and multiplex methodology, standard molecular biology techniques including immunoblotting and RT-PCR, as well as ex vivo models of haematopoiesis. It is anticipated that experience will also be acquired with in vivo models of haematological malignancy.

How to apply for this project

This project will be based in Bristol Medical School - Translational Health Sciences in the Faculty of Health Sciences at the University of Bristol.

Please visit the Faculty of Health Sciences website for details of how to apply