Hemochromatosis, Erythrocytosis and the JAK2 p.V617F Mutation

Hereditary hemochromatosis (HH) is an inherited iron overload disorder, particularly prevalent in Irish and Scandinavian populations (1), characterised by abnormal iron metabolism, leading to excess iron deposition in the parenchymal cells of the liver, heart, and endocrine organs. HH is commonly associated with mutations in the HFE gene and in other genes such as HJV, that regulate the biology of hepcidin, a key regulator of iron homeostasis, and TRF2 that is responsible for uptake of transferrin bound iron (2, 3). A rare but recurrent hematological manifestation of HH is a raised hematocrit due to an excess of red cells (erythrocytosis) possibly an important clue to an underlying hepatoma (4). Therapy is based on the removal of excess iron by phlebotomy or erythrocytapharesis, with ferritin levels used to monitor treatment effectiveness (5). The most common cause of acquired primary erythrocytosis is the myeloproliferative neoplasm polycythemia vera (PV). Approximately 95% of PV patients harbour the JAK2 p.V617F mutation. In hematopoietic stem cells, this mutation leads to constitutively activated, intracellular JAK-STAT signalling resulting in increased production of red and white blood cells and platelets. For many years the mainstay of PV therapy has been Corresponding author: Stephen E. Langabeer, Ph.D., FRCPath Cancer Molecular Diagnostics Central Pathology Laboratory St. James’s Hospital Dublin 8, Ireland Phone: +35 314103576 Fax: +35 314103513 E-mail: [email protected]