Investigating the Interactions Between Bone Marrow Macrophages and Acute Myeloid Leukaemia

Moore, Jamie (2022) Investigating the Interactions Between Bone Marrow Macrophages and Acute Myeloid Leukaemia. Doctoral thesis, University of East Anglia.

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Abstract

Acute myeloid leukaemia (AML) is a heterogeneous and lethal malignancy that currently has no cure. Even in patients that can undergo intensive chemotherapies often relapse due to minimal residual disease sequestered within the bone marrow (BM) microenvironment. The BM microenvironment is a highly complex organ to allow support of haematopoiesis via regulation of the haematopoietic stem cells (HSC). HSC reside in specific niches and are regulated by many cell types, such as BM macrophages. In AML, BM macrophages interact with leukaemic cells to promote AML progression, via regulation of phagocytosis. Phagocytosis in macrophages can occur through LC3, termed LC3 associated phagocytosis (LAP). Impairment of LAP has been shown to supress solid tumour growth, however, the role of LAP in AML has not been defined. In this thesis, I investigated the role of LAP in BM macrophages within the BM microenvironment of AML.

This research shows that depletion of BM macrophages increased AML growth and that LAP is the predominate method that is used to phagocytose dying cells in the AML microenvironment. Inhibition of LAP led to accumulation of apoptotic debris in the BM, resulting in accelerated leukaemic growth. Mechanistically, LAP of AML apoptotic bodies (ABs), by BM macrophages, resulted in STING activation. Mitochondria from AML ABs were processed by BM macrophages via LAP. Moreover, mitochondrial DNA from AML ABs was responsible for the induction of STING activation in BM macrophages. STING activation suppressed AML growth via increased phagocytosis potential in BM macrophages. Furthermore, the phosphatidylserine recognition receptor TIM4 is required for the control of AML growth and the expression of TIM4 in LAP deficient BM macrophages is reduced. Together, these findings show how BM macrophages interact with apoptotic AML cells to supress AML growth in a LAP dependent mechanism.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Chris White
Date Deposited:	01 Dec 2022 10:55
Last Modified:	01 Dec 2022 10:55
URI:	https://ueaeprints.uea.ac.uk/id/eprint/89980
DOI:

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