Leukemia cells that have internalized exosomes (red) released by bone marrow stromal cells. Image credit: Javidi-Sharifi et al. (CC BY 4.0)
Leukemias are cancers of white blood cells. The cells grow and divide rapidly, often because of mutations in proteins called kinases. Since the kinase mutations do not occur in healthy cells, they provide a good target for anti-leukemia drugs. Several such kinase inhibitors are effective at treating leukemia patients. However, most leukemia cells develop ways to resist the effects of the kinase inhibitors over time, leading to relapses of the disease.
One way that leukemia cells resist kinase inhibitors is by taking advantage of signals coming from supportive cells, known as stromal cells, in the bone marrow. When patients are treated with kinase inhibitors, the bone marrow stromal cells produce more of a signaling protein called FGF2. The leukemia cells then use FGF2 to survive the effects of the kinase inhibitors.
It was not clear how the FGF2 signal reaches the leukemia cells from the bone marrow stromal cells. Now, using biochemical techniques, Javidi-Sharifi, Martinez et al. show that bone marrow stromal cells package FGF2 into small compartments called exosomes. The stromal cells release the exosomes into the bone marrow, and the leukemia cells then engulf and internalize the exosomes. Leukemia cells that had taken up FGF2 in this way were better able to survive kinase inhibitor treatment than leukemia cells that had not.
Javidi-Sharifi, Martinez et al. also observed that FGF2 also affects the bone marrow stromal cells themselves, causing them to grow faster, produce more FGF2 and release more exosomes. Blocking the effects of FGF2 on the stromal cells slowed their growth and caused fewer exosomes to be released. In addition, mice whose bone marrow stromal cells could not produce FGF2 survived leukemia for longer than mice whose stromal cells provided protective FGF2 in exosomes to leukemia cells. This suggests that taking advantage of drugs that prevent bone marrow stromal cells from releasing FGF2 in exosomes might improve treatments for leukemia. Further research will be needed to confirm whether this strategy would be effective in humans.
