Trio of leukemias share a single mutation

" said Gilliland. "We thought it was a good bet that the cause would be a constitutively activated tyrosine kinase." According to Gilliland, while PV, ET and MMM are rare, their prevalence is about five times higher than CML, with about 100,000 cases in the U.S. each year.

The researchers performed high-throughput DNA sequence analysis of blood and mouth-swab samples from 164 PV patients, 115 ET patients and 46 MMM patients. The patients were recruited via a notice posted on the web site of an advocacy group for people with myeloproliferative disease. The researchers used a sequencing technique developed in collaboration with co-authors William Sellers and Matthew Myerson of Dana-Farber. Specifically, they sequenced regions of tyrosine kinases that were likely to be mutated in the leukemias.

Their sequencing analysis revealed that about 75 percent of the PV patients, 32 percent of the ET patients and 35 percent of the MMM patients showed the same defect in the gene for a tyrosine kinase known as JAK2.

"There are some similarities among these three different diseases, and some overlap in the diagnostic criteria, but it was a surprise to us that the same mutation appears to account for at least a fraction of cases for all three," said Gilliland

By comparing the DNA sequences from the blood with those from the mouth swabs, the researchers could determine which mutations the blood cell progenitors had acquired -- since the mouth-swab DNA represents inherited germline DNA that had not undergone mutation. Their comparisons revealed that the characteristic mutation in JAK2 was acquired, not inherited. And since the researchers did not find the mutation in a large number of normal blood samples, they were able to conclude that the mutation was characteristic of a large fraction of the three leukemias.

JAK2 normally functions as a molecular switch to trigger proliferation of red blood cells in response to events such as blood loss, said Gilliland. Al

Contact: Jim Keeley
Howard Hughes Medical Institute

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