Allen, Hermione Elsie;
(2025)
The Role of the Bone Marrow Immune Niche
in Preventing Relapse in Adult B-ALL
Following Reduced Intensity Conditioning
Allogeneic-HSCT.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Reduced intensity-conditioning (RIC) allogeneic haematopoietic stem cell transplants (alloHSCT) improved event-free survival for patients > 40 years old, as established by the UKALL14 (NCT01085617) trial for patients with B-cell acute lymphoblastic leukaemia (B-ALL). Persistence or reappearance of minimal residual disease is a strong predictor of relapse after RIC alloHSCT in ALL and is associated with ineffective graft-versus-leukaemia (GVL) responses by donor T cells. In this thesis, I sought to characterise differences in the bone marrow (BM) immune cell composition from adult patients with B-ALL who underwent RIC alloHSCT with or without subsequent relapse. I first identified using mass cytometry, and confirmed using single RNA-sequencing (scRNA-seq), an enrichment in early CD4+ T cell subsets in the BM T cell compartments of patients in remission who later relapsed (CR→Rel) compared to patients who remained in long term remission (CR→CR), post-alloHSCT. However, low sample sizes meant that conclusions lacked statistical power. Furthermore, I also identified an inflammatory myeloid signature using bulk RNA-sequencing, which was further characterised in scRNA-seq in patients who later relapsed, which potentially represented a functional pro-inflammatory immature neutrophil population. Cell-cell interactome analysis predicted increased pro-inflammatory signalling pathways in CR→Rel compared to CR→CR, further suggesting a chronically inflamed BM prior to relapse post-alloHSCT. Investigation of the BM at B-ALL diagnosis identified a similar myeloid signature in patients who eventually relapsed. Further interrogation of this signature in a 150-patient UKALL14 validation cohort identified a significant correlation of the myeloid signature with EFS at diagnosis, however this was not an independent predictor of outcome when adjusted for age. In summary, my thesis identified BM immune signatures potentially associated with future relapse after RIC alloHSCT for B-ALL, and my data may suggest that a myeloid signature is enriched in both the diagnostic and post-alloHSCT samples of patients destined to relapse, which could be supported by its correlation with age and EFS in a large diagnostic cohort.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The Role of the Bone Marrow Immune Niche in Preventing Relapse in Adult B-ALL Following Reduced Intensity Conditioning Allogeneic-HSCT |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2025. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10203811 |
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