dc.contributor.author | Pyzer, Athalia Rachel | |
dc.date.accessioned | 2018-05-03T13:04:45Z | |
dc.date.available | 2018-05-03T13:04:45Z | |
dc.date.issued | 2017-03-21 | |
dc.date.submitted | 2018-05-03T12:05:55.414Z | |
dc.identifier.citation | Pyzer, A.R. 2017. Myeloid-derived Suppressor Cells in Acute Myeloid Leukaemia. Queen Mary University of London | en_US |
dc.identifier.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/36704 | |
dc.description | PhD | en_US |
dc.description.abstract | The tumour microenvironment consists of an immunosuppressive niche created by the
complex interactions between cancer cells and surrounding stromal cells. A critical
component of this environment are myeloid-derived suppressor cells (MDSCs), a
heterogeneous group of immature myeloid cells arrested at different stages of
differentiation and expanded in response to a variety of tumour factors. MDSCs exert
diverse effects in modulating the interactions between immune effector cells and
malignant cells. An increased presence of MDSCs is associated with tumour progression,
poorer outcomes, and decreased effectiveness of immunotherapeutic strategies.
In this project, we sought to quantify and characterise MDSC populations in patients
with Acute Myeloid Leukaemia (AML) and delineate the mechanisms underlying their
expansion. We have demonstrated that immune suppressive MDSCs are expanded in
the peripheral blood and bone marrow of patients with AML. Furthermore, AML cells
secrete extra-cellular vesicles (EVs) that skew the tumour microenvironment from
antigen-presentation to a tumour tolerogenic environment, through the expansion of
MDSCs. We then demonstrated that MDSC expansion is dependent on tumour and EV
expression of the oncoproteins MUC1 and c-Myc. Furthermore, we determined that
MUC1 signalling promotes c-MYC expression in a microRNA (miRNA) dependent
mechanism. This observation lead us to elucidate the critical role of MUC1 in
suppressing microRNA-genesis in AML, via the down-regulation of the DICER protein, a
key component of miRNA processing machinery. Finally, exploiting this critical pathway,
we showed that MDSCs can be targeted by MUC1 inhibition or by the use of a novel
hypomethylating agent SGI-110. | en_US |
dc.description.sponsorship | British Society for Haematology
Royal College of Physicians, UK
Professor David Avigan and the department of Bone Marrow Transplantation. | en_US |
dc.language.iso | en | en_US |
dc.publisher | Queen Mary University of London | en_US |
dc.rights | The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author | |
dc.subject | Acute Myeloid Leukaemia | en_US |
dc.subject | myeloid-derived suppressor cells | en_US |
dc.subject | tumour microenvironment | en_US |
dc.title | Myeloid-derived Suppressor Cells in Acute Myeloid Leukaemia | en_US |
dc.type | Thesis | en_US |