Acute Myeloid Leukaemia Drives Metabolic Changes in the Bone Marrow Niche

Abstract

Acute myeloid leukaemia (AML) is a highly proliferative cancer characterised by infiltration of immature haematopoietic cells in the bone marrow (BM). AML predominantly affects older people and outcomes, particularly in this difficult to treat population remain poor, in part due to inadequate response to therapy, and treatment toxicity. Normal haematopoiesis is supported by numerous support cells within the BM microenvironment or niche, including adipocytes, stromal cells and endothelial cells. In steady state haematopoiesis, haematopoietic stem cells (HSCs) primarily acquire ATP through glycolysis. However, during stress-responses HSCs rapidly transition to oxidative phosphorylation, enabled by mitochondrial plasticity. Historically it was thought that cancer cells preferentially used glycolysis for ATP production, however recently it has become evident that many cancers, including AML primarily use the TCA cycle and oxidative phosphorylation for rapid proliferation. AML cells hijack the stress-response pathways of their non-malignant counterparts, utilising mitochondrial changes to drive expansion. In addition, amino acids are also utilised by leukaemic stem cells to aid their metabolic output. Together, these processes allow AML cells to maximise their ATP production, using multiple metabolites and fuelling rapid cell turnover which is a hallmark of the disease. This review of AML derived changes in the BM niche, which enable enhanced metabolism, will consider the important pathways and discuss future challenges with a view to understanding how AML cells are able to hijack metabolic pathways and how we may elucidate new targets for potential therapies.

Keywords: acute myeloid leukaemia; adipocytes; bone marrow niche; free fattty acids; metabolism.

Figure 1

Schematic of BM niche. The complexity of the niche is highlighted showing many cell types and interaction between these cells to facilitate blood production. Mesenchymal stem cells differentiate into BM adipocytes, stromal cells, endothelial cells and osteoblasts (green arrow). Mesenchymal derived cells supports HSC differentiation (red arrows) in to blood progenitor cells (blue arrows).

Figure 2

Schematic of AML metabolic of bone marrow microenvironment. Acute Myeliod Leukaemia (AML) is able to manipulate the surrounding environment to enhance its own metabolism. (A) In response to the increase energy demanding, AML produces NOX2 derived superoxide, whichacts on BM stormal cells to activate mitochondrial transfer. Mitochondrial uptake by AML is enable through tunneleing nanotubules by the transmembrane glycoprotien CD38. (B) AML manipulates adipocytes inducing phosphorylation of lipase, to activate lipolysis and te release of Free Fatty Acids (FFA). AML is able to icrease FFa uptake via increased expression of CD38 and fatty-acid binding protiens (FABPs). (C) To prevent the activation of apoptotic pathways, AML outsources its waste mitochondria. This process of outsourcing mitophagy utilises the macrophages in the microenvionment.