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Leukemia Drug Turns Mini-Molecules Up, Cancer Genes Down

that they are also important for normal differentiation.”

In this study, the researchers used leukemia cells grown in the laboratory and cells donated by patients to study how the drug ATRA affects miRNA levels and how those changes affect the cells.

The investigators exposed the leukemia cells to the drug for up to 96 hours, causing the cells to mature. The treatment increased the level of eight miRNAs and a drop in one compared with untreated cells.

Of these, the researchers focused on miRNA-15b and miRNA-16-1, which are known to regulate the activity of the Bcl-2 gene. They found that high levels of the two miRNAs were associated with low Bcl-2 activity.

Next, they showed that the two miRNAs actually caused the drop in Bcl-2 activity. They did this by adding additional amounts of the two miRNAs to leukemia cells not treated with ATRA. Restoring the miRNAs caused a strong drop in Bcl-2 levels.

The researchers then looked at miRNA let-7, a known regulator of the Ras oncogene, and likewise found that high levels of this miRNA were associated with low Ras activity.

They established a cause and effect relationship as before, by adding additional let-7 to untreated leukemia cells.

“Overall,” Garzon says, “our findings show that ATRA induces the expression of these three miRNAs, and through them regulates genes that need to be silenced for the cell to differentiate.”

Funding from the National Cancer Institute, the Paul and Mary Haas Chair in Genetics, a Lauri Strauss Discovery grant award, the Kimmel Foundation and the CLL Global Research Foundation supported this research.

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