Myeloproliferative neoplasm (MPN) is characterized by unrestrained mature myeloid cell production followed by exhaustion of hematopoiesis, bone marrow fibrosis, splenomegaly, and debilitating constitutional symptoms.  A somatically acquired mutation at JAK2V617F or in calreticulin (CALR), present at the level of the hematopoietic stem cell, is a characteristic feature of MPN yet the exact role these mutations play in disease pathogenesis is unclear. 

The genetic background in which JAK2V617F cells reside is an important modifier of MPN disease manifestation both in humans and in murine MPN models. Moreover, therapy with the JAK1/2 inhibitor ruxolitinib reduces spleen size and relieves constitutional symptoms without significantly decreasing the JAK2V617F allele burden. Together, these data implicate non-JAK2V617F cells as key mediators of disease in MPN.

Lymphocytes are key cytokine producers, mediators of autoimmunity, and have been implicated as the responsible party driving fibrosis in many non-MPN experimental systems. Disturbances in T cell subset balances are observed in patients with autoimmune mediated fibrotic diseases, and so it is feasible that lymphocytes are responsible for some of the pathologic features of MPN, for example the splenomegaly, excessive inflammatory cytokine profile, and bone marrow fibrosis.

We are now investigating the role of lymphocytes in MPN pathogenesis, both in MPN model systems and primary MPN patients. We hope that this work may lead to novel therapeutic targets for MPN patients. Understanding the role of lymphocytes in MPN may also reveal the mechanism by which JAK inhibitors impact some clinical aspects of MPN without affecting the JAK2V617F neoplastic burden.