Investigating the link between acute myeloid leukaemia and the dysregulation of liver metabolism

Maynard, Rebecca (2024) Investigating the link between acute myeloid leukaemia and the dysregulation of liver metabolism. Doctoral thesis, University of East Anglia.

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Abstract

Acute myeloid leukaemia (AML) is a highly proliferative, metabolically plastic haematological malignancy. There is currently no cure and even after treatments patients often relapse. AML is addicted to fatty acid (FA) for proliferation, survival, and treatment resistance. Bone marrow (BM) adipose tissue is utilised and depleted by AML, although AML can also access FA from peripheral blood. The liver is the master regulator of FA metabolism in the body via storage, de novo generation and secretion back into the blood. Signals from tissues around the body modify hepatocyte FA metabolism, increasing or decreasing availability of serum FA. In this thesis I investigate how BM AML induces changes to FA metabolism in the liver.

This study shows that AML induces systemic metabolic changes within a murine model. During BM AML progression, mice lost bodyweight, and proportional weight of the inguinal and gonadal fat pads, and serum FA were elevated. Bulk RNA sequencing showed that AML engraftment significantly reduced expression of FA metabolism and peroxisome proliferator-activated receptor (PPAR) pathways in the liver, this was confirmed by gene and protein analysis in the livers of engrafted mice. Treatment of primary murine hepatocytes with media conditioned by AML cells further showed downregulated gene expression, FA uptake and respiration. Furthermore, analysis of mouse serum and conditioned media showed increased hepatocyte growth factor (HGF) and IL-1β, which also downregulated FA metabolism in vivo and in vitro. Moreover, knockdown (KD) of Hgf in AML blasts mildly restored FA metabolism gene expression and reduced blast FA uptake in vivo. Pparα expression was also downregulated and, as HGF has been shown to act on PPARα, AML engrafted mice were treated with the PPARα agonist fenofibrate. Treatment reduced tumour burden, mildly restored liver FA metabolism gene expression, and increased serum FA. These findings show that AML secreted HGF downregulates liver FA metabolism via a PPARα dependent mechanism.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences
Depositing User:	Kitty Laine
Date Deposited:	17 Mar 2025 13:45
Last Modified:	17 Mar 2025 13:45
URI:	https://ueaeprints.uea.ac.uk/id/eprint/98760
DOI:

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