Protein kinase C-β-dependent changes in the glucose metabolism of bone marrow stromal cells of chronic lymphocytic leukemia.

Survival of chronic lymphocytic leukemia (CLL) cells critically depends on the support of an adapted and therefore appropriate tumor microenvironment (TME). Increasing evidence suggests that B-cell receptor associated kinases such as protein kinase C (PKC)-β or Lyn kinase, are essential for the formation of a microenvironment supporting leukemic growth. Here, we describe the impact of PKCβ on the glucose metabolism in bone marrow stromal cells (BMSC) upon CLL contact. BMSC get activated by CLL contact expressing stromal PKCβ that diminishes mitochondrial stress and apoptosis in CLL cells by stimulating glucose uptake. In BMSC, the upregulation of PKCβ results in increased mitochondrial depolarization and leads to a metabolic switch towards oxidative phosphorylation. Additionally, PKCβ-deficient BMSC regulates the expression of Hnf1 promoting stromal insulin signaling after CLL contact. Our data suggest that targeting PKCβ and the glucose metabolism of the leukemic niche could be a potential therapeutic strategy to overcome stroma-mediated drug-resistance. © AlphaMed Press 2021 SIGNIFICANCE STATEMENT: The bystander relationship between cancer cells and BMSC leads to pro-survival activities of BMSC, like the expression of stromal PKCβ, which contributes to cancer growth and progression. Increasing evidence highlights that leukemic cells can modify metabolic pathways of neighboring cells in order to satisfy their energy demands. Therefore, the metabolic characterization of the tumor microenvironment might give us new strategies to target the microenvironment as an alternative to cytotoxic therapies. Here, we can show for the first time a link between stromal metabolism and PKCβ expression in BMSC after contact to primary CLL cells.