JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response Journal Article
| Authors: | Kleppe, M.; Kwak, M.; Koppikar, P.; Riester, M.; Keller, M.; Bastian, L.; Hricik, T.; Bhagwat, N.; McKenney, A. S.; Papalexi, E.; Abdel-Wahab, O.; Rampal, R.; Marubayashi, S.; Chen, J. J.; Romanet, V.; Fridman, J. S.; Bromberg, J.; Teruya-Feldstein, J.; Murakami, M.; Radimerski, T.; Michor, F.; Fan, R.; Levine, R. L. |
| Article Title: | JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response |
| Abstract: | The identifi cation 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 myelofi brosis and improves overall survival; however, the mechanism by which JAK inhibitors achieve effi cacy has not been delineated. Patients with MPN present with increased levels of circulating proinfl ammatory cytokines, which are mitigated by JAK inhibitor therapy. We sought to elucidate mechanisms by which JAK inhibitors attenuate cytokine-mediated pathophysiology. Single-cell profi ling demonstrated that hematopoietic cells from myelofi brosis models and patient samples aberrantly secrete infl ammatory cytokines. Pan-hematopoietic Stat3 deletion reduced disease severity and attenuated cytokine secretion, with similar effi cacy 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. © 2015 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 5 |
| Issue: | 3 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2015-03-01 |
| Start Page: | 316 |
| End Page: | 331 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-14-0736 |
| PROVIDER: | scopus |
| PMCID: | PMC4355105 |
| PUBMED: | 25572172 |
| DOI/URL: | |
| Notes: | Export Date: 2 April 2015 -- Source: Scopus |
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