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JAK-STAT Pathway Activation in Malignant and Non-Malignant Cells Contributes to MPN Pathogenesis and Therapeutic Response

Kleppe, Maria and Kwak, Minusk and Koppikar, Priya and Riester, Markus and Keller, Matthew and Bastian, Lennart and Hricik, Todd and Bhagwat, Neha and Abdel-Wahab, Omar and Marubayashi, Sachie and Chen, Jonathan and Romanet, Vincent and Fridman, Jordan and Bromberg, Jacqueline and Murakami, Masato and Radimerski, Thomas and Michor, Franziska and Fan, Rong and Levine, Ross (2015) JAK-STAT Pathway Activation in Malignant and Non-Malignant Cells Contributes to MPN Pathogenesis and Therapeutic Response. Cancer discovery, 5 (3). pp. 316-331. ISSN 2159-8290; 2159-8274

Abstract

The presence of JAK-STAT pathway mutations1-5 in myeloproliferative neoplasm (MPN) patients led to clinical trials of JAK kinase inhibitors, including the JAK1/2 inhibitor ruxolitinib6,7. Ruxolitinib therapy reduces splenomegaly and systemic symptoms in myelofibrosis (MF) and is associated with an improvement in overall survival8-10, however the mechanisms by which JAK inhibitors achieve clinical benefit in MF have not been delineated. MPN patients present with increased levels of circulating pro-inflammatory cytokines, and the increase in systemic cytokines is reversed with JAK inhibitor therapy11,12. We therefore sought to delineate the mechanisms by which JAK inhibitors attenuate cytokine production in MF. Here we show that JAK inhibition inhibits cytokine production in malignant and non-malignant cells. Single cell proteomic profiling demonstrated that hematopoietic cells from MF mice produce a spectrum of inflammatory cytokines. Pan-hematopoietic Stat3 deletion improved survival, reduced disease severity, and reduced cytokine secretion, with efficacy similar to that observed with ruxolitinib therapy. By contrast, restricting loss of Stat3 to the malignant clone did not reduce disease severity or cytokine production in vivo. Consistent with these findings, we found that both malignant and non-malignant cells secrete inflammatory cytokines, and that JAK inhibition reduces cytokine production from both tumor and non-tumor populations. Our results demonstrate that JAK-STAT3 mediated cytokine production from malignant and non-malignant cells contributes to MPN pathogenesis and that inhibition of JAK-STAT signaling in both populations is required for therapeutic efficacy.

Item Type: Article
Date Deposited: 12 Oct 2016 00:45
Last Modified: 12 Oct 2016 00:45
URI: https://oak.novartis.com/id/eprint/11429

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