Change is stressful. The change that a healthy blood stem cell undergoes to become a leukemia stem cell (LSC) is no exception, think of healthy blood stem cells as young professionals and the transformation into an LSC as having a child.
Now, these chronically frazzled LSCs need a special stress-relief technique above and beyond what they used to require. And the LSC equivalent of yoga and chardonnay is a process called mitophagy. LSCs desperately need mitophagy.
A University of Colorado Cancer Center study published today in the journal Cell Stem Cell identifies an essential switch that LSCs use to activate mitophagy. Think of AMPK like a babysitter without it; there is no yoga or chardonnay.
When researchers turned off AMPK, it was as if they had canceled the babysitter and there was no mitophagy. Thus, without AMPK allowing the stress release of mitophagy, LSCs were very literally stressed to death. It points to a potential sea change in the way doctors treat acute myeloid leukemia.
"The standard of care for acute myeloid leukemia hasn't changed since the 1960s. This study and the concept of targeting leukemia stem cells, in general, could help us offer new treatments for this most common form of adult leukemia," said Craig T. Jordan, Ph.D., an investigator at University of Colorado Cancer Center.
Acute myeloid leukemia
Work in the Jordan lab by postdoctoral fellow and paper first author Shanshan Pei, Ph.D., shows there is another genetic player here, namely the gene FIS1. It directly turns on mitophagy.
But FIS1 is also very difficult to manipulate. Luckily, AMPK turns on FIS1, which turns on mitophagy, and AMPK is much easier to mess with. And turning off AMPK turns off FIS1, which turns off mitophagy.
"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 cell," said Jordan.
"If we can translate this concept to patients, the potential for improved therapy is fascinating," said Jordan. In fact, Jordan points out the CU program is unique in its focus on laboratory and clinical research designed to target cancer stem cells specifically.
"Over the past five years I've worked closely with Dr. Daniel Pollyea, the clinical director of our leukemia services, to create a bench-to-bedside program in which we only evaluate therapies with the potential to kill the heart of leukemic disease the leukemia stem cell," Jordan said.