JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response
Paper by Raajit K. Rampal indexed on Europe PMC as PubMed record 25572172, in Cancer Discovery (2015), one of the most cited records naming an author with this name at Memorial Sloan Kettering Cancer Center.
Overview
Unlabelled: 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.
Indexed on Europe PMC as PubMed record 25572172 (DOI 10.1158/2159-8290.cd-14-0736). Its author list gives "Rampal R" with the affiliation "Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York", which names Memorial Sloan Kettering Cancer Center; that is how the record was matched to Raajit K. Rampal, and no figure has been checked by an editor.
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