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Discoveries Reveal Gene Mutation That Causes Blood Disorders

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Several members of the American Society of Hematology (ASH) have discovered a single point mutation in the JAK2 gene that is expressed in a high percentage of patients with one of three myeloproliferative diseases (MPDs).

The discovery of this mutation may lead to the development of a targeted therapy to combat these disorders.

The three main MPDs are polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis.

Kenneth Kaushansky, M.D., professor and chair of the Department of Medicine at the University of California, San Diego, will lead a special plenary session on the origins and effects of these JAK2 disorders at the 47th Annual Meeting of ASH.

"There has been an explosion of new knowledge beginning with the discovery earlier this year of the role of the JAK2 V617F mutation in polycythemia vera, myelofibrosis, and essential thrombocythemia, providing novel insight into the molecular basis of pathological myeloproliferation," said Dr. Kaushansky.

"Because this discovery reveals key information about the pathophysiology of MPDs, it was decided that the issue should be discussed before all attendees of the ASH annual meeting."

JAK2 is a protein tyrosine kinase, an enzyme that adds a phosphate group to numerous cellular proteins involved in transmitting growth signals that trigger the production of blood cells.

The V617F mutation causes the constitutive activation of these molecular signaling pathways, leading to the uncontrolled cell proliferation for which the myeloproliferative disorders are named.

Abnormal regulation or function of tyrosine kinases have been implicated in many cancers, including chronic myelogenous leukemia (CML), the treatment of which was revolutionized with the discovery of imatinib mesylate (commonly known as Gleevec).

Imatinib mesylate targets the tyrosine kinase responsible for the abnormal proliferation of white blood cells that characterizes this disease.

A research team led by Anthony Green, M.D., of Cambridge University noted that the JAK2 mutation occurs in most patients with polycythemia vera, but only half of those with essential thrombocythemia and idiopathic myelofibrosis.

Dr. Green's analysis revealed JAK2 mutation status divided essential thrombocythemia into two biologically distinct subtypes with those patients carrying the V617F mutation having disease characteristics that closely resembled polycythemia vera.

"Our results suggest that V617F-positive essential thrombocythemia and polycythemia vera are closely related and have major implications for the classification, diagnosis, and management of MPDs," according to Dr. Green.

Researchers from the Mayo Clinic and Dana-Farber Cancer Institute also examined the relationship between essential thrombocythemia and polycythemia vera relating to the JAK2 mutation.

Essential thrombocythemia patients with the V617F mutation had disease characteristics commonly associated with polycythemia vera, but they were unsure whether that was relevant when selecting the best treatment option.

"More research needs to be completed, but we may be on the brink of developing targeted therapies to treat MPDs," says Dr. Kaushansky.

"The identification of a potential molecular target is a major discovery that may one day benefit patients, but not all MPD patients have the JAK2 mutation."

"Researchers are continuing to look for other mutations that may be associated with MPDs."

"It is hoped that open discussion of new findings and remaining questions will spur additional insights into the origins and control of these disorders."