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Mass Spec Enables Researchers to Identify Mutation Linked to AML; Could Lead to Dx for PGx Treatments

Researchers from five US academic labs and Cell Signaling Technology used phosphopeptide immunoprecipitation and mass spectrometry to link a new mutation in a tyrosine kinase gene to acute myeloid leukemia.
Though the results were strictly pre-clinical and were meant only to find the mutation, “the hope is that it will eventually be used for more diagnostic purposes in the clinic,” said Jeffrey Tyner, a co-author of the study and postdoc in the lab of Brian Druker at Howard Hughes Medical Institute.
Specifically, the mutation, a tyrosine kinase allele called JAK3A572V, could encourage sponsors to develop drugs or diagnostics that target this mutation. JAK3 is in good company: A decade ago Druker helped discover a tyrosine kinase inhibitor that would go on to become Gleevec, which treats chronic myeloid leukemia.
This new research, published in this month’s Cancer Cell, is notable because it used mass spec to identify cancer targets where more common approaches, including DNA sequence analysis, would yield few cancer alleles. Additionally, the results could interest Pfizer, which is currently developing a tyrosine kinase inhibitor that targets this particular mutation but for a different indication.
“In the case of AML, all evidence at this point seems to be that there’s going to be a lot of very infrequent mutations that are causing this disease, and if you have a newly diagnosed patient who comes into the clinic there needs to be a way to figure out which of these infrequent mutations is causing their disease,” Tyner told ProteoMonitor last week. “It’s hoped that this technology [phosphopeptide immunoprecipitation and LC-MS/MS mass spec] as well others can be used for this purpose.”
To reach their findings, the researchers used phosphopeptide mass spec to analyze murine AML cell lines known to have constitutive STAT5 phosphorylation. They chose STAT5 because it appears in around 70 percent of all AML cases.
This enabled them to identify an activating mutation in the JAK3 pseudokinase domain in the murine CMK acute megakaryoblastic leukemia cell line, a new finding.
“Mass spectrometric assessment of phosphopeptides that denote constitutive activation of signal-transduction pathways may provide a useful surrogate screen for functional activation of cancer disease alleles that are, in turn, therapeutic targets,” the researchers write in their paper.

“Mass spectrometric assessment of phosphopeptides that denote constitutive activation of signal transduction pathways may provide a useful surrogate screen for functional activation of cancer disease alleles that are, in turn, therapeutic targets.”

Equally important, because AML patients who don’t have a mutation in JAK3 will “probably” have one in another tyrosine kinase, the “goal” of the study is “to unravel what most of these [mutations] are and use the technology to figure out which one the patient has,” Tynder said. This could be an uphill fight because around 90 proteins comprise the tyrosine kinase family.
Is It Druggable?
Previously identified JAK3 mutations have been loss-of-function mutations associated with a “severe combined immunodeficiency,” which could mean that JAK3 inhibitors could play a role in treating autoimmune disorders, including asthma, rheumatoid arthritis, and inflammatory bowel disease.
Indeed, Pfizer is currently studying whether a JAK3 inhibitor can be used as an immunosuppressor to help prevent acute allograft rejection in kidney transplant patients.
But the Cancer Cell paper suggests that the same JAK3 inhibitor “may also have clinical activity in AMKL patients with mutant activating alleles of JAK3, and potentially in T cell lymphoma/leukemia.”
Cell Signaling Technology, which used Thermo Electron mass specs in the Cancer Cell study, said it is in talks with Pfizer about its JAK3 research and is currently sharing information, according to Christopher Bunker, director of business development at Cell Signaling Technology.  He declined to elaborate.
“We’ve made them well aware of the technology and they’re actively investigating how they can be applied to their programs,” Bunker told ProteoMonitor.
AML is the most common type of leukemia and accounts for more than 11,900 new cases in the US each year, according to the National Marrow Donor Program.

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