Itchy mast cells in MPNs

In this issue of Blood, Ishii and colleagues investigate the role of mast cells in the pathogenesis of pruritus in patients with MPNs.

The BCR-ABL–negative myeloproliferative neoplasms (MPNs) of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are characterized by a predisposition to thrombosis and hemorrhage, risk of blastic transformation, and premature death. In addition to these serious consequences, myeloproliferative disorder patients suffer variable constitutional symptoms, such as fatigue, bone pain, night sweats, and pruritus.¹  Data gathered from 1179 MPN patients reported that 81% suffer from pruritus, and this symptom was present in 72%, 84%, and 85% of ET, PMF, and PV patients, respectively.¹  The intensity of the pruritus can be severe, frequently exacerbated by water (ie, aquagenic pruritus), and has led some patients to discontinue bathing or to commit suicide in intractable cases. Therapy of MPN pruritus has been empiric, with antihistamines sometimes providing relief. Additionally, the use of selective serotonin reuptake inhibitors has been helpful,²  and has suggested that platelets (the repository for serotonin in the blood) may have a role in MPN pruritus.

The pathogenesis of constitutional symptoms and particularly pruritus in MPN remains uncertain, despite recent insights into some aspects of molecular pathogenesis with identification of mutations that affect the JAK-STAT pathway including the JAK2^V617F, mutations in the 12th exon of JAK2, and mutations in cMPL.³  Increased JAK2 allele burden has been associated with a greater burden of pruritus among PV patients,⁴  although the exact mechanism for this association has remained uncertain, with speculation focusing on increased peripheral blood levels of cytokines. Additionally, investigators have investigated the various subsets of leukocytes that might be increased or activated in MPN patients. An association between the JAK2 mutation in basophils from PV patients, basophil activation, and degranulation with disease-associated pruritus was presented at the 2008 American Society of Hematology annual meeting.⁵  Further work defining the role of basophils in the pathogenesis of MPN pruritus is ongoing.

Mast cells contain a variety of mediators of the inflammatory response (ie, histamine, tryptase, prostaglandins, and leukotrienes) that can generate pruritus. Ishii et al isolate peripheral blood mast cells as well as generating mast cells from CD34⁺ cells of MPN patients suffering from pruritus, while not on cytoreductive therapy.⁶  In their article in this issue of Blood, they make several salient observations. The first is that mast cells arising from MPN patients were functionally different from normal control mast cells in that they release greater levels of pruritogenic factors. Second, they observe that among patients with the most severe pruritus, (1) more mast cells are generated from CD34⁺ cells, (2) their mast cells are less prone to apoptosis, and (3) they have more marked increases in release of potentially pruritogenic cytokines. Finally, through use of the MPN mutation analysis, they demonstrate that mast cells from MPN patients are indeed offspring of the malignant clone, potentially explaining their functional differences from normal mast cells. These observations identify an intriguing target for therapy among MPN patients with significant pruritus, and further expand our knowledge of functional changes in leukocytes seen in MPN patients.

There is now accumulating evidence that mast cells, basophils, and even platelets may all play a role in MPN pruritus. Intriguingly, preliminary reports of JAK2 inhibitor therapy report significant decreases in pruritus,⁷  and we can be hopeful that further discoveries regarding the pathogenesis of MPN pruritus may yield additional insight into the overall pathogenesis of MPNs.