Their findings implicate a protein called Mushashi that prevents cells from maturing, creating a large population of immature cells, which is one of the hallmarks of CML. This same molecular pathway may also be related to other aggressive leukemias, as well as solid tumors like glioblastoma (a severe form of brain cancer) and breast cancer.
With collaborators at other institutions, the Duke team looked at 120 human specimens from patients representing different phases of CML progression. They found that Musashi levels increased dramatically as the disease became more aggressive.
"We found high levels of Musashi in all of the human advanced phase CML samples we studied,” said senior author Tannishtha Reya, an associate professor of pharmacology and cancer biology at Duke. “The fact that this pattern was seen in all of the human cells, regardless of patients’ gender or ethnicity, and in people on three continents, marked it as potentially a major signal that needed to be studied in as much depth as possible,” Reya said.
Because CML progression is marked by a block in cell maturation (called differentiation) and an increase in immature cells, the team wanted to learn whether this was driven by an aberrant reversal of the signals that regulate cell differentiation. They focused on Numb, a molecule that is known to control differentiation during normal development.
The team used mice to compare the chronic (less harmful) and blast-crisis (most harmful and severe) phases of CML. They found much lower levels of Numb in the blast-crisis phase mice.
"It is not always clear if a pathway that appears to be important in mouse models will be relevant in human disease," Reya said. "In this case, however, the data and patterns are so strong in human patient samples that pursuing these findings becomes critical."
This led them to explore the way that Numb was being repressed in advanced disease, and whether this repression contributes to the maintenance of blast-crisis phase. They focused on the RNA-binding protein Musashi, which had previously been shown to repress Numb in other systems.
Reya's team found that Musashi is particularly elevated in stem cells and needed for their growth, which could help explain why it is co-opted to promote the growth of immature cells in cancers as well. Musashi expression was 10 times higher in the more immature blast crisis CML phase. It may be a target for future therapies because blocking Mushashi could block cancer growth, Reya said.
MEDICA.de; Source: Duke University Medical Center