Researchers use phosphoproteome to target cancer

Scientists scanned the phosphoprotein profile of acute myeloid leukemia (AML), identifying a novel mutant protein kinase (JAK3) that may drive AML progression

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DANVERS, Mass.—In a recent issue of Cancer Cell, scientists at Cell Signaling Technology (CST), Oregon Health Science University (OHSU) and Boston's Brigham & Women's Hospital scanned the phosphoprotein profile of acute myeloid leuke­mia (AML), identifying a novel mutant protein kinase (JAK3) that may drive AML progres­sion. Aside from providing scientists with a new lead on a debilitating cancer, the discov­ery also offers proof of the effi­cacy of a new CST proteomics platform called PhosphoScan.
"Because tyrosine phosphor­ylation is commonly abnormal in cancer cells, and because this abnormally high tyrosine phosphorylation is very often involved in driving the prolif­eration of cancer cells, we felt that this technology would be ideal for identification of cancer targets," says Dr. Jeffrey Tyner, OHSU scientists and co-author of the study.
The platform works by first isolating phosphorylated pro­teins via immunoprecipitation. This subset of proteins is then fractionated and identified using standard liquid chromatogra­phy and tandem mass spec­trometry (LC-MS/MS). By sub­dividing samples in this manner, researchers focus their efforts on the hundreds of key signal­ing molecules in which they are interested without the morass of background proteins.
"The strategy of using PhosphoScan to quickly reveal the profile of essentially every active and phosphorylated tyrosine kinase in a cell or tis­sue sample provides a huge breakthrough in our ability to determine cancer mechanisms in cell lines and human tumors," said CST CSO Dr. Roberto Polakiewicz in a prepared state­ment.
According to Tyner, PhosphoScan offers several advantages over DNA sequence analysis. "First, it provides information about the phos­phorylation (activation) status of proteins in the cell," he says. "So it actually tells us from a functional standpoint what is happening inside the cells. DNA sequencing simply logs sequence variations that may or may not change the function of the protein. Hence we can narrow down the field of possible candidate genes much more easily by screening the proteins than by screening the DNA sequence, and the number of false-positive results is much smaller.
"Second, in terms of time, it would take several years to sequence all of the tyrosine kinase genes in even a small cohort of patients," he adds. "This mass spec approach can be performed in a matter of weeks."
It is not clear how many patients suffer from JAK3-driven cancers, Tyner says, although the number is likely not large. In that subset of patients, however, inhibitors that block the activity of JAK3 could be very effective treatments. JAK3 inhibitors are already being tested for treatment of autoimmune dis­orders, so these are potentially the first therapeutics to try on these forms of leukemia.
"In the long run, we would like to try to apply this technology in the clinics as well," Tyner says. "The hope would be that a newly diagnosed patient could be tested using this technology to determine the identity of their specific genetic abnormality, and we could then treat them with a specific inhibitor [to control] their disease."

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