Mutation on trio of leukemias signals drug target
caused by acquired mutations that alter a specific enzyme
controlling blood cell proliferation. Identifying the genetic
malfunction may give rise to a targeted therapy, similar to chronic
myelogenous leukemia (CML), which is treated with Gleevec.
The three leukemias, polycythemia vera (PV), essential thrombocythemia (ET) and myeloid metaplasia with myelofibrosis (MMM), affect as many as 100,000 people in the United States.
The research team, analysed the blood of patients with the three leukaemias for a defect that permanently activated a particular type of enzyme called a tyrosine kinase.
Tyrosine kinases are cellular switches that control an array of cellular processes. The researchers concentrated on the enzymes because activated tyrosine kinases had been shown to cause other similar myeloproliferative diseases such as CML.
"The three disorders that we studied were the last of these diseases whose causes had not yet been discovered," said Gary Gilliland, head researcher at the Howard Hughes Medical Institute (HHMI). "We thought it was a good bet that the cause would be a constitutively activated tyrosine kinase."
While PV, ET and MMM are rare, their prevalence is about five times higher than CML, with about 100,000 cases in the US 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 researchers used a sequencing technique, sequencing regions of tyrosine kinases that were likely to be mutated in the leukaemias.
Their sequencing analysis revealed that about 75 per cent of the PV patients, 32 per cent of the ET patients and 35 per cent 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. 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 leukaemias.
JAK2 normally functions as a molecular switch to trigger proliferation of red blood cells in response to events such as blood loss. Abnormal activation of the gene for JAK2 would be expected to lead to myeloproliferative disease.
In test tube studies, the researchers found a drug that inhibits the JAK2 tyrosine kinase did inhibit growth of cells with the mutant JAK2 gene.
The findings suggest that inhibition of this kinase, just as Gleevec inhibits the kinase that causes CML, might be an effective therapeutic approach for these diseases. The characteristic mutation will have diagnostic value in distinguishing the myeloproliferative diseases from secondary causes of similar blood cell pathologies, such as smoking or cardiac disorders.
Gilliland and his team published its findings on March 24, 2005, in an immediate early publication in the journal >Cancer Cell.
