Metabolism in stem cell driven leukaemia: parallels between haematopoiesis and immunity

Abstract

Our understanding of cancer metabolism spans from its role in cellular energetics and supplying the building blocks necessary for proliferation, to maintaining cellular redox and regulating the cellular epigenome and transcriptome. Cancer metabolism, once thought to be solely driven by upregulated glycolysis, is now known to comprise of multiple pathways with great plasticity in response to extrinsic challenges. Furthermore, cancer cells can modify their surrounding niche during disease initiation, maintenance and metastasis, contributing to therapy resistance. Leukaemia is a paradigm model of stem cell driven cancer. Here, we review how leukaemia remodels the niche and rewires its metabolism with particular attention paid to therapy-resistant stem cells. Specifically, we aim to give a global, non-exhaustive overview of key metabolic pathways. By contrasting the metabolic rewiring required by myeloid leukaemic stem cells with that required for haematopoiesis and immune cell function, we highlight the metabolic features they share. This is a critical consideration when contemplating anti-cancer metabolic inhibitor options, especially in the context of anti-cancer immune therapies. Finally, we examine pathways that have not been studied in leukaemia but are critical in solid cancers in the context of metastasis and interaction with new niches. These studies also offer detailed mechanisms that have yet to be investigated in leukaemia. Given that cancer (and normal) cells can meet their energy requirements by not only upregulating metabolic pathways, but also utilising systemically available substrates, we aim to inform how interlinked these metabolic pathways are, both within leukaemic cells and between cancer cells and their niche.