Target acute leukemia cells in hypoxic bone marrow microenvironment by suppressing mitochondrial metabolic remodelling

In childhood acute lymphoblastic leukemia (ALL), residual leukemic cells persisting in the bone marrow after the first 4 weeks of therapy are termed as minimal residual disease (MRD). These cells are presumed to resistant to the therapy, but why these cells survive while the rest die remains unclear. The bone marrow microenvironment has low oxygen levels (hypoxia). We have recently shown that bone marrow microenvironment induce mitochondrial redox adaptation and confer multidrug resistance to ALL cells. Targeting this redox adaptation process could restore chemosensitivity in drug resistant cells. In on-going experiments, we found that bone marrow microenvironment help ALL cells respond to hypoxia stress and evolve a stress resistant phenotype. Surviving cells, i.e MRD cells, adapt to the stress by reducing energy requirements and increasing the levels of survival (anti-apoptotic) proteins and antioxidants. This stress adaptation also protected against stress induced by chemotherapy, partially through AMPK/Foxo3a/MnSOD2 signalling pathways. Drugs such as Metformin (used in type II diabetes) and Bay 87-2443, which target the mitochondrial respiratory function and cellular hypoxic response, overcome metabolic adaptation and restore chemosensitivity. Thus targeting metabolic adaptation in ALL may lead to the development of new therapeutic strategies for chemoresistance and relapse in childhood ALL.

Grant Award – Kidscan Pump Priming Grant (2016)
Funding Award – £5,000
Funding Awarded To – Dr Jizhong Liu
Research Location – University of Manchester
Lead Researcher – Dr Jizhong Liu