BMM influence on metabolism
Bone marrow microenvironment influence on ALL cell metabolism
Our lab models the protective bone marrow niche using co-cultures containing ALL cell lines and primary human bone marrow stromal cells (BMSC) or osteoblast (HOB) adherent layers. Employing this model we have observed a population of ALL cells that migrates beneath adherent layers, which are termed phase dim (PD) tumor cells, that have a quiescent phenotype and are resistant to chemotherapy. We observed dramatic changes in the active form of both protein kinase B (AKT) and AMP-activated protein kinase (AMPK), key metabolic regulators that have been shown to control protein synthesis and lipid metabolism respectively, in PD tumor cells compared to tumor cells grown in media alone. In addition, PD cells have a higher rate of glycolysis compared to cells grown in media alone. Along with providing ATP, glycolysis has the ability to produce intermediates for macromolecule synthesis, a critical step for cells poised to proliferate. We hypothesize that the increase in macromolecule synthesis in the PD population leads to a “priming effect” which positions the PD cells to proliferate more quickly after detachment from adherent layers. Changes in the metabolism of this resilient population may provide novel targets for treatments aimed at sensitizing resistant ALL cells in the bone marrow microenvironment thus reducing minimal residual disease and minimizing the chances of relapse.