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Blood, 4 June 2009, Vol. 113, No. 23, pp. 5942-5950.
Prepublished online as a Blood First Edition Paper on February 4, 2009; DOI 10.1182/blood-2008-09-179416.
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Submitted September 16, 2008
Accepted January 28, 2009
Pivotal role of mast cells in pruritogenesis in patients with myeloproliferative disorders
Takefumi Ishii, Jiapeng Wang, Wei Zhang, John Mascarenhas, Ronald Hoffman, Ying Dai, Nathaniel Wisch, and Mingjiang Xu*
Division of Hematology/Oncology, Tisch Cancer Institute and Departments of Medicine, Mount Sinai School of Medicine, New York, NY, United States
The Myeloproliferative Disorders Research Consortium, New York, NY, United States
* Corresponding author; email: mingjiang.xu{at}mssm.edu.
Pruritus is a common symptom in patients with Philadelphia chromosome negative myeloproliferative disorders (MPDs). The pathophysiology of MPD-associated pruritus is unclear. We have demonstrated that MPD-mast cells (MCs) are involved by the malignant process. In the present study, we explored the hypothesis that MCs play an important role in the development of pruritogenesis in MPDs. We found that MPD MCs released significantly greater amounts of pruritogenic factors including histamine, leukotrienes and IL-31 than normal MCs. Elevated levels of IL-31 were also observed in MPD CD3+ cell-conditioned media. MPD MCs exhibited increased migratory behavior in response to stem cell factor or interleukin-8, which was associated with increased filamentous-actin content. Furthermore, the presence of pruritus in MPDs was statistically correlated with a greater number of MCs being generated by CD34+ cells; a greater number of MC-colonies being formed by CD34+ cells; decreased apoptosis and prostaglandin D2 release by cultured MCs; and higher plasma levels of IL-31. These data demonstrate that functional abnormalities of MPD MCs likely lead to pruritogenesis in patients with MPDs. These studies provide cellular and molecular targets for the development of anti-pruritus drug(s) for patients with MPDs.
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