Cells With JAK2 Mutation Respond To Tyrosine Kinase Inhibitor

NEW YORK (Reuters Health) - Cells with a constitutively activated tyrosine kinase mutation unique to three types of leukemia respond to a small molecule tyrosine kinase inhibitor, with reduced proliferation and induction of apoptosis, a research team has found.

Earlier this year, another group of investigators reported that a single point mutation in the JAK2 tyrosine kinase, JAK2V617F, is prevalent in patients with polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (MMM). (See Reuters Health report March 17, 2005.)

The current study, by Dr. Gary Gilliland and colleagues, published in the March 24th online issue of Cancer Cell, independently confirms this finding.

Dr. Gilliland of Harvard Medical School, Boston and colleagues identified the polymorphism in the blood of 50% of 171 patients with PV, 37% of 126 with ET, and 13% of 46 with MMM.

Sequence analysis of DNA from buccal swabs showed that the JAC2V617F allele was absent in 96% of samples, providing, say the investigators, "strong genetic evidence that JAK2V617F is an acquired somatic disease allele that arises in hematopoietic progenitors and confers a selective growth advantage."

In functional assays, the polymorphism led to constitutively activated tyrosine kinase when expressed in 293T cells. Expression of the mutated allele conferred erythropoietin hypersensitivity and erythropoietin-independent survival.

In a leukemic cell line expressing JAK2V617F, but not other leukemia cells, treatment with JAK inhibitor 1 showed a dose-dependent inhibition of proliferation and induction of apoptosis.

The researchers conclude that JAK2V617F may have "diagnostic and therapeutic value in myeloproliferative diseases." They also point out that JAK-STAT pathway activation is also found in some solid tumors, "and thus genotypic analysis of JAK family members in solid tumors may also be warranted."

Source: Cancer Cell 2005. [ Google search on this article ]

MeSH Headings: Polymorphism, Single Nucleotide

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