2007.11.12 – JAK2-V617F or JAK2 exon 12 mutations

11/12/2007 8:29:42 AM

Medical Edge — New research may help in treating blood disorder

Tribune Media Services

DEAR MAYO CLINIC: I was diagnosed with polycythemia vera six years ago. It was discovered when I had an emergency appendectomy. My spleen was enlarged. Are there new treatments for this disease? Any new research?

Polycythemia vera is a blood disorder in which your bone marrow makes too many red blood cells. In some cases, it also may result in production of too many white blood cells and platelets. But, it’s the excess red blood cells that thicken one’s blood and cause most of the health concerns associated with the disorder, such as an enlarged spleen and increased risk of blood clots.

Signs and symptoms of the disorder can include skin itchiness and redness, headaches, shortness of breath, dizziness, sudden numbness, weakness or paralysis on one side, and tingling, burning or weakness in your hands, feet, arms or legs.

Polycythemia vera is a chronic condition, and there is no cure. Treatment, which hasn’t changed substantially in the last 30 years, usually involves reducing the number of red blood cells by drawing blood from a vein (phlebotomy). How often you need phlebotomy depends on the severity of your condition. If phlebotomy isn’t enough to control symptoms or complications, medication is sometimes used to decrease the number of red blood cells or suppress the bone marrow’s ability to produce blood cells.

Because of recent research, however, the prospects of a major change in treatment in the next five to 10 years are high.

In 2005, researchers discovered that approximately 95 percent of people with polycythemia vera have a change (mutation) in the DNA that starts in a single cell in the bone marrow, known as JAK2-V617F. It is not an inherited mutation, but is acquired sometime after conception. The mutation affects a protein “switch” that normally tells cells when and how to grow and divide. This mutant cell, and all the cells generated by it, have an adverse effect on your blood cell production.

The same cell mutation was found in a majority of people with two other blood disorders: essential thrombocythemia, which results in an overproduction of platelets, and primary myelofibrosis, which affects bone marrow.

In 2007, another set of mutations, called JAK2 exon 12, was found in patients with polycythemia vera who did not have JAK2-V617F. This research seems to show that almost all patients with polycythemia vera carry either JAK2-V617F or JAK2 exon 12 mutations. When studied in the laboratory, both mutations produced a polycythemia vera-like disease in mice. Therefore, it’s reasonable to consider the possibility that a drug that blocks JAK2 could benefit patients with polycythemia vera.

Recently, Mayo Clinic investigators participated in a study that found an oral drug that strongly inhibited JAK2 in laboratory-maintained cell cultures and in mice with JAK2-V617F-induced polycythemia. Early-phase human studies with anti-JAK2 drugs have also begun. At this time, these studies only include people with primary myelofibrosis who are at high risk of complications from the disease. However, researchers anticipate that future studies will include people with essential thrombocythemia and polycythemia vera. — Ayalew Tefferi, M.D., Hematology, Mayo Clinic, Rochester.