Molecular Changes and Biomarkers in Chronic Myeloproliferative Disorders

The three main chronic myeloproliferative disorders are polycythemia vera (PV), essential
thrombocythemia (ET) and idiopathic myelofibrosis (IMF). These are clonal neoplastic
diseases characterized by proliferation of one or more hematopoietic lineages. Recently a
mutation of the Janus Kinase 2 (JAK2) gene that leads to the substitution of phenylalanine
for valine at position 617 of the JAK2 protein, JAK2 V617F, has been found in 76% to 97% of
patients with PV, 29% to 57% of patients with ET and 50% of patients with IMF. This mutation
confers constitutive activity on to the JAK2 protein and appears to play an important role
in the pathobiology of these conditions. However, not all patients with myeloproliferative
disorders have this mutation and it may not be the primary cause of these diseases. The
primary goal of this prospective natural history study is to investigate the molecular basis
of these diseases in groups of patients who have JAK2 V617F and in those who do not. A
second goal is to identify biomarkers for PV and the other myeloproliferative disorders that
are easier to measure than JAK2 V617F. Approximately, 150 patients with myeloproliferative
disorders will be studied over 3 years. The studies will involve the collection of 40 mL to
50 mL of peripheral blood from each subject. The blood will be used to assess neutrophil
gene and protein expression, gene polymorphisms, and plasma protein levels.

- INCLUSION CRITERIA:

1. Diagnosis or suspected diagnosis of PV, ET, or IMF. The World Health
Organization Criteria will be used for diagnosing this disorder. In brief, the
criteria for PV is hemoglobin greater than 18.5 g/dL in men and greater than
16.5 g/dL in women and splenomegaly on palpation in the absence of secondary
erythrocytosis. If splenomegaly is absent, the patient must have 2 of the
following 4 minor criteria: platelet count greater than 400 x 10(9)/L, leukocyte
count greater than 12 x 10(9)/L, marrow biopsy with trilineage increase in
cellularity, and low serum erythropoietin level. The criteria for EF is a
platelet count greater than 600 x 10(9)/L with no known cause of reactive
thrombocytosis and a normal hemoglobin. The criteria for IMF is fibrosis of the
bone marrow and splenomegaly without preceding PV, ET or chronic myelogenous
leukemia.

2. Both male and female subjects will be studied.

3. Any ethnic group.

4. 18 years of age or older.

EXCLUSION CRITERIA:

Subjects will be excluded if they have any of the following conditions:

1. Increased blood counts due to a disease other than chronic myeloproliferation.

2. Know history of anemia (hematocrit less than 12.0 mg/dL).

3. Pregnancy.

4. Infection with HIV, hepatitis B, or hepatitis C.