Education, Science of CML

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Discovery suggests possible treatment strategy for aggressive leukemias

DURHAM, N.C. – Researchers at Duke University Medical Center have identified a

mechanism that could explain how patients move into the worst phase of chronic

myelogenous leukemia (CML).

Their findings implicate a protein called Mushashi (named after a Samurai)

warrior 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, Ph.D., 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. The work appears in Nature online on July 18.

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.

The Musashi protein was named for a Samurai warrior who fought with two swords,

because the loss of Musashi in fruit flies (where the gene was discovered)

resulted in a developmental defect in which flies had double bristles,

reminiscent of Musashi's swords.

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.

My computer went off for upgrading and lost the URL where I found the article.

FYI,

Lottie Duthu