Metabolic Dynamics in Hematological Malignancies

Hematological malignancies encompass a diverse array of blood cancers in which metabolic reprogramming plays a pivotal role in sustaining malignant proliferation, survival under microenvironmental stress and therapy resistance. Tumour cells co-opt glycolysis to generate biosynthetic precursors, yet many also exploit mitochondrial oxidative phosphorylation and tricarboxylic acid (TCA) cycle intermediates to meet heightened energy demands. Glutamine and fatty acids serve as alternative fuels, with enzymes such as glutaminase and pyruvate carboxylase directing substrate flux into the TCA cycle via anaplerotic reactions. Interactions with the bone marrow niche—including stromal adipocytes—further shape metabolic plasticity, enabling malignant stem cell populations to persist and drive relapse. Understanding these dynamic pathways has uncovered targetable vulnerabilities, informing the development of inhibitors that disrupt energy production, redox balance and biosynthetic capacity in leukaemia and lymphoma subtypes.

Research from Nature Portfolio

Recent studies have shown that persistent chronic myeloid leukaemia stem cells maintain elevated pyruvate anaplerosis despite tyrosine kinase inhibitor therapy, driven by upregulated mitochondrial pyruvate carrier and pyruvate carboxylase activity. Pharmacological blockade of the carrier complex reinstates metabolic control and sensitises leukaemic stem cells to standard treatment. In acute myeloid leukaemia, investigations into cells co-cultured with bone marrow adipocytes revealed that inhibition of fatty acid β-oxidation using a novel lipid-derived compound induces apoptosis in monoculture but elicits a compensatory switch to glycolysis in the adipocyte niche. Crucially, combining fatty acid oxidation blockade with cytarabine produces synergistic leukaemia cell killing under microenvironmental conditions, highlighting the value of dual metabolic and cytotoxic targeting.

Metabolic Dynamics in Hematological Malignancies publication trend

The graph below shows the total number of articles in metabolic dynamics in hematological malignancies across all publications each year (not limited to Nature Index journals).

Technical terms

Anaplerosis: The process by which intermediates of the TCA cycle are replenished to sustain biosynthesis and energy production.

Leukemic stem cell (LSC): A subpopulation of leukaemia cells with self-renewal capacity responsible for disease initiation and relapse.

Oxidative phosphorylation (OXPHOS): The mitochondrial process that generates ATP through electron transport and proton gradient utilisation.

Fatty acid β-oxidation (FAO): The stepwise catabolism of fatty acids in mitochondria to produce acetyl-CoA and support energy metabolism.

Tricarboxylic acid (TCA) cycle: A central metabolic pathway that oxidises acetyl-CoA to generate reducing equivalents for ATP synthesis.

Glutaminase (GLS): An enzyme that converts glutamine to glutamate, fuelling the TCA cycle and biosynthetic pathways in cancer cells.

References

1. Fatty Acid Metabolism, Bone Marrow Adipocytes, and AML. Frontiers in Oncology (2020).
2. Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells. Nature Communications (2023).
3. Inhibition of FAO in AML co-cultured with BM adipocytes: mechanisms of survival and chemosensitization to cytarabine. Scientific Reports (2018).
4. PDP1 is a key metabolic gatekeeper and modulator of drug resistance in FLT3-ITD-positive acute myeloid leukemia. Leukemia (2023).
5. Mitochondrial metabolism as a potential therapeutic target in myeloid leukaemia. Leukemia (2021).
6. Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes. Oncotarget (2016).