Metabolism in stem cell-driven leukemia: parallels between hematopoiesis and immunity

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 tran-scriptome. Cancer metabolism, once thought to be solely driven by upregulated glycolysis, is now known to comprise multiple pathways with great plasticity in response to extrinsic challenges. Furthermore, cancer cells can modify their surrounding niche during disease initiation, maintenance, and metastasis, thereby contrib-uting to therapy resistance. Leukemia is a paradigm model of stem cell-driven cancer. In this study, we review how leukemia remodels the niche and rewires its meta-bolism, 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- leukemic stem cells with that required for hematopoiesis and immune cell function, we highlight the metabolic features they share. This is a critical consideration when contemplating anticancer metabolic inhibitor options, especially in the context of anticancer immune therapies. Finally, we examine pathways that have not been studied in leukemia but are critical in solid cancers in the context of metastasis and interaction with new niches. These studies also offer detailed mechanisms that are yet to be investigated in leukemia. Given that cancer (and normal) cells can meet their energy requirements by not only upregulating metabolic pathways but also utilizing sys-temically available substrates, we aim to inform how interlinked these metabolic pathways are, both within leukemic cells and between cancer cells and their niche.

Automated summary

Our understanding of cancer metabolism encompasses its role in cellular energetics, providing building blocks for proliferation, regulating cellular redox and epigenome, and responding to extrinsic challenges. Cancer cells can modify their microenvironment and acquire therapy resistance. In this study, we focus on how leukemia remodels the niche and rewires its metabolism, with emphasis on therapy-resistant stem cells. We also examine metabolic pathways shared by leukemic stem cells, hematopoiesis, and immune cell function, which is crucial for selecting anticancer metabolic inhibitors, especially in the context of immune therapies.