Functional Abnormalities Of Mast Cells From Patients With Myeloproliferative Disorders And Their Role In Pruritogenesis

The Philadelphia chromosome negative myeloproliferative disorders (MPDs) are clonal hematologic malignancies frequently associated with JAK2 mutation (JAK2V617F). Pruritus is common in MPDs with an incidence of ~50%. The pathophysiology of MPD-associated pruritus is unclear. We hypothesize that mast cells (MCs) play a critical role in the pruritogenesis in MPDs.We demonstrated that MPD MCs were involved by the malignant clone in MPDs using JAK2V617F, MplW515L and chromosomal abnormalities as clonality markers. MPD MCs exhibited increased migration ability and are characterized by increased apoptosis. The pruritogenic mediator release by MPD MCs such as histamine and leukotrienes were elevated; while the level of an anti-pruritogenic factor, prostaglandins D2 release by MPD MCs were shown to be decreased at higher temperature. In addition, pruritus was associated with a greater number of MCs generated by CD34+ cells, a lower number of apoptotic MCs and a lower level of PGD2 release in patients with MPDs. Furthermore, a JAK2 inhibitor, erlotinib, effectively suppressed the MC colony formation by MPD CD34+ cells.These data indicate that abnormal MCs might play an important role in the pruritogenesis in MPDs. These studies will likely result in the identification of cellular and molecular targets for the treatment of MPD-associated pruritus.