JAK–STAT Pathway Activation in Malignant and Nonmalignant Cells Contributes to MPN Pathogenesis and Therapeutic Response
| Autor: | Jordan S. Fridman, Efthymia Papalexi, Maria Kleppe, Jonathan J. Chen, Raajit K. Rampal, Matthew D. Keller, Priya Koppikar, Vincent Romanet, Minsuk Kwak, Neha Bhagwat, Markus Riester, Rong Fan, Ross L. Levine, Franziska Michor, Julie Teruya-Feldstein, Todd Hricik, Omar Abdel-Wahab, Anna Sophia McKenney, Thomas Radimerski, Jacqueline Bromberg, Masato Murakami, Sachie Marubayashi, Lennart Bastian |
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| Rok vydání: | 2015 |
| Předmět: |
Ruxolitinib
Myeloproliferative Disorders Janus kinase 2 biology Janus kinase 1 medicine.medical_treatment medicine.disease Article Proinflammatory cytokine STAT Transcription Factors Cell Transformation Neoplastic Cytokine Oncology Immunology biology.protein medicine Cancer research Animals Humans Cytokine secretion Myelofibrosis Janus kinase Janus Kinases Signal Transduction medicine.drug |
| Zdroj: | Cancer Discovery. 5:316-331 |
| ISSN: | 2159-8290 2159-8274 |
| DOI: | 10.1158/2159-8290.cd-14-0736 |
| Popis: | The identification of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) has led to the clinical development of JAK kinase inhibitors, including ruxolitinib. Ruxolitinib reduces splenomegaly and systemic symptoms in myelofibrosis and improves overall survival; however, the mechanism by which JAK inhibitors achieve efficacy has not been delineated. Patients with MPN present with increased levels of circulating proinflammatory cytokines, which are mitigated by JAK inhibitor therapy. We sought to elucidate mechanisms by which JAK inhibitors attenuate cytokine-mediated pathophysiology. Single-cell profiling demonstrated that hematopoietic cells from myelofibrosis models and patient samples aberrantly secrete inflammatory cytokines. Pan-hematopoietic Stat3 deletion reduced disease severity and attenuated cytokine secretion, with similar efficacy as observed with ruxolitinib therapy. In contrast, Stat3 deletion restricted to MPN cells did not reduce disease severity or cytokine production. Consistent with these observations, we found that malignant and nonmalignant cells aberrantly secrete cytokines and JAK inhibition reduces cytokine production from both populations. Significance: Our results demonstrate that JAK–STAT3-mediated cytokine production from malignant and nonmalignant cells contributes to MPN pathogenesis and that JAK inhibition in both populations is required for therapeutic efficacy. These findings provide novel insight into the mechanisms by which JAK kinase inhibition achieves therapeutic efficacy in MPNs. Cancer Discov; 5(3); 316–31. ©2015 AACR. See related commentary by Belver and Ferrando, p. 234 This article is highlighted in the In This Issue feature, p. 213 |
| Databáze: | OpenAIRE |
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