The characteristic of both cancer and cell division is altered metabolism. For example, chronic lymphocytic leukemia (CLL) cells move between lymph nodes (LNs) and peripheral blood (PB), where they are exposed to proliferative and survival-promoting signals from neighboring cells. However, knowledge of LN CLL metabolism and its impact on therapy response was sparse.

For a study, researchers used a two-tiered approach to understand CLL LN metabolism. First, they took PB samples from 8 patients at baseline and 3 months after receiving ibrutinib (IBR) treatment, which drives CLL cells to leave LNs. In order to simulate the LN microenvironment, they utilized in vitro B-cell receptor (BCR) or CD40 stimulation and carried out metabolomic and transcriptome investigations.

The combined analysis showed that the LNs underwent significant alterations in purine, glucose, and glutamate metabolism. Tricarboxylic acid cycle (TCA), energy generation, and amino acid metabolism were primarily controlled by CD40 signaling. BCR signaling ideally activated numerous biosynthetic pathways and glucose and glycerol metabolism. Pathway analysis showed that IBR therapy and in vitro stimulation had opposing effects. In accord, BCR/CD40 activation led to the induction of the metabolic regulator MYC and its target genes, which IBR then inhibited. Then, 13C fluxomics on CD40/BCR-stimulated cells demonstrated that glucose was predominantly metabolized into lactate and ribose-5-phosphate while glutamine was a major fuel source for the TCA cycle.

Finally, V9302 reduced CD40/BCR-induced resistance to venetoclax via inhibiting glutamine import. When taken as a whole, the results provided light on significant metabolic abnormalities induced by the CLL LN microenvironment. The TCA cycle frequently uses amino acids as fuel, which raises the possibility of novel therapeutic weaknesses.