Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms

Ofir Wolach, Rob S. Sellar, Kimberly Martinod, Deya Cherpokova, Marie McConkey, Ryan J. Chappell, Alexander J. Silver, Dylan Adams, Cecilia A. Castellano, Rebekka K. Schneider, Robert F. Padera, Daniel J. DeAngelo, Martha Wadleigh, David P. Steensma, Ilene Galinsky, Richard M. Stone, Giulio Genovese, Steven A. McCarroll, Bozenna Iliadou, Christina HultmanDonna Neuberg, Ann Mullally, Denisa D. Wagner, Benjamin L. Ebert

Research output: Contribution to journalArticlepeer-review

Abstract

Thrombosis is a major cause of morbidity and mortality in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), clonal disorders of hematopoiesis characterized by activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. Neutrophil extracellular trap (NET) formation, a component of innate immunity, has been linked to thrombosis. We demonstrate that neutrophils from patients with MPNs are primed for NET formation, an effect blunted by pharmacological inhibition of JAK signaling. Mice with conditional knock-in of Jak2V617F, the most common molecular driver of MPN, have an increased propensity for NET formation and thrombosis. Inhibition of JAK-STAT signaling with the clinically available JAK2 inhibitor ruxolitinib abrogated NET formation and reduced thrombosis in a deep vein stenosis murine model. We further show that expression of PAD4, a protein required for NET formation, is increased in JAK2V617F-expressing neutrophils and that PAD4 is required for Jak2V617F-driven NET formation and thrombosis in vivo. Finally, in a population study of more than 10,000 individuals without a known myeloid disorder, JAK2V617F-positive clonal hematopoiesis was associated with an increased incidence of thrombosis. In aggregate, our results link JAK2V617F expression to NET formation and thrombosis and suggest that JAK2 inhibition may reduce thrombosis in MPNs through cell-intrinsic effects on neutrophil function.

Original languageEnglish
Article numberaan8292
JournalScience Translational Medicine
Volume10
Issue number436
DOIs
StatePublished - 11 Apr 2018

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