This article is more than 5 years old. Information may no longer be current.

Researchers explore implications of JAK2 in myeloproliferative disorders

For half of patients, a somatic mutation in JAK2 may lead to the onset of a myeloproliferative disorder.

Issue: February 1, 2006

Add topic to email alerts

Receive an email when new articles are posted on

Please provide your email address to receive an email when new articles are posted on .

Subscribe

Added to email alerts

You've successfully added to your alerts. You will receive an email when new content is published.

Click Here to Manage Email Alerts

You've successfully added to your alerts. You will receive an email when new content is published.

Click Here to Manage Email Alerts

Back to Healio

We were unable to process your request. Please try again later. If you continue to have this issue please contact customerservice@slackinc.com.

Back to Healio

Scientists presented startling findings last year: A single nucleotide mutation signaling kinase Janus Kinase (JAK)2 was found in most patients with polycythemia vera and about half of patients with idiopathic myelofibrosis and essential thrombocythemia. Since that presentation at the March 2005 meeting of the Cell Biology of Megakaryocytes and Platelets conference in Buelton, Calif., additional researchers have rushed to interpret those results.

“A short time later, four papers appeared within five weeks of one another, detailing the clinical, molecular, genetic in vitro and in vivo consequences of this mutation,” said Kenneth Kaushansky, MD, chair of the department of medicine at the University of California, San Diego. He spoke at a special plenary session held at the 47th Annual Meeting of the American Society of Hematology in Atlanta.

“This finding has already begun to revolutionize how we think about and diagnose this disease and will hopefully revolutionize how we treat patients with these disorders of blood cell production and function,” he said.

Diagnostic difficulties

Diagnosing the various myeloproliferative disorders is challenging, said Josef T. Prchal, MD, from the Baylor College of Medicine in Houston. Clinicians have difficulty differentiating myeloproliferative disorders from reactive processes. Further, the various myeloproliferative disorders, such as chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia and agnogenic myeloid metaplasia with myelofibrosis, are difficult to characterize.

For instance, major diagnostic criteria for polycythemia vera include elevated red blood cell mass, normal oxygen saturation and an enlarged spleen. However, some patients with polycythemia vera do not meet those criteria but develop thromboses and other complications prior to their diagnosis. So researchers are searching for additional diagnostic variables.

“We need other measures to reflect the biology of this disease,” Prchal said. The JAK2-V617F somatic mutation is an important contributor to the polycythemia vera pathophysiology. It explains a great deal of abnormal cell behavior, but it does not appear to be a disease-initiating polycythemia vera mutation.

Clinical consequences of JAK2-V617F include secondary fibrosis (P = .004), bleeding (P = .015) and thrombosis (P = .026), said Radek C. Skoda, MD, from the University Hospital Basel in Switzerland.

Mitotic recombination

Skoda is researching how JAK2 affects the pathogenesis of myeloproliferative disorders and the clinical consequences of the mutation, which he believes to be somatic.

His team mapped the chromosomal region where this occurs by looking at patients with a loss of heterozygosity (LOH) on chromosome 9p. Mapping this region would ideally provide a road map to the specific gene. They also questioned the mechanism behind the JAK2 mutation.

“One explanation is that the tip of chromosome 9 is lost,” Skoda said. Mitotic recombination, a rare type of mytosis, could also be the culprit. When the gene splits, there is an exchange of material that creates two types of daughter cells. Because one of the two alleles is lost, one cell has a proliferative advantage.

Individuals with 9pLOH have two copies of the gene, which suggests mitotic recombination causes the loss of heterozygosity in those with myeloproliferative disorders.

Skoda predicted that somatic mutation in JAK2 could cause myeloproliferative disorders for half of those patients. The heterozygous cells would then undergo mitotic recombination, leading to the homozygous JAK2-VG17F mutation.

The other half of patients with myeloproliferative disorders probably have a mutation in an unidentified gene that could cause those disorders, Skoda said.

It’s possible that some patients with the mutation could remain in this stage without progression. Other patients could acquire the heterozygous JAK2 mutation and then, following mitotic recombination, become homozygous for JAK2-V617F.

Researchers are speculating that if patients have a somatic mutation in JAK2, then a specific JAK2 inhibitor could cure the disease in about half of those with myeloproliferative disorders.

According to an allele-specific polymerase chain reaction assay, about 83% of patients with polycythemia vera, 58% of patients with idiopathic myelofibrosis and 55% of patients with essential thrombocythemia had the JAK2 mutation. Therefore, a somatic mutation likely occurs in these patients, Skoda said.

Kaushansky added that abnormalities of hematopoietic growth factors, their receptors or the signals they initiate might underlie chronic myeloproliferative disorders.

Research is ongoing to explore the possible causes and consequences of the JAK2 mutation. – by Rebekah Cintolo

For more information:

• Kaushansky K, Vainchenker V, Skoda RC, et al. Special Plenary Session. Myeloproliferative diseases revealed: the molecular basis and potential for targeted therapy of polycythemia vera, idiopathic myelofibrosis, and essential thrombocythemia. Presented at: 47th Annual Meeting of the American Society of Hematology; Dec. 10-13, 2005; Atlanta.