Leukemia stem cells (LSCs) are believed to initiate the development of acute myeloid leukemia as well as relapse following chemotherapy. However effective methods to selectively eradicate LSCs are yet to be discovered. New findings the University of Colorado Cancer Center may offer a possible solution. According to research team’s work in Cell Stem Cell, by targeting the mitochondria, LSC’s could literally be stressed to death.
"In various situations, mitochondria may need to be destroyed. Really, it's the mitochondria saying, 'I need to eat myself.' Typically, the reason they need to eat themselves is when they're damaged," says senior study co-author Craig T. Jordan.
Mitochondria become stressed when a healthy cell transforms into an LSC. To maintain its cellular health, the LSCs activate a mitophagy pathway that breaks down the stressed or damaged mitochondria. In their studies, the team finds that a regulator protein known as FIS1 plays a key role in regulating the pathway.
“Depletion of FIS1 attenuates mitophagy and leads to inactivation of GSK3, myeloid differentiation, cell cycle arrest, and a profound loss of LSC self-renewal potential,” the team reports.
However, as the team also finds, FIS1 is also very difficult to manipulate. They instead have turned to another protein, the kinase AMPK. AMPK works upstream, directly regulating F1S1.
When the team turned off AMPK, F1S1 was downregulated, and mitophagy in LSCs was ultimately turned off. AMPK may thus serve as a potential target for selectively attacking LSCs for leukemia therapy.
"Leukemia stem cells require AMPK for their survival, but normal hematopoietic cells can do without it. The reason this study is so important is that so far nobody's come up with a good way to kill leukemia stem cells while sparing normal blood-forming cells. If we can translate this concept to patients, the potential for improved therapy is very exciting," said Jordan.
Image: A graphical abstract showing AMPK as an upstream regulator of FIS1. AMPK activation helps drive mitophagy that leads to LSC progression to leukemia. Image courtesy of Craig Jordan, Cell Stem Cell.