Effects of JAK1/2 inhibition on bone marrow stromal cells of myeloproliferative neoplasm (MPN) patients and healthy individuals. (30th April 2018)

• Record Type: Journal Article
• Authors: Zacharaki, Dimitra; Ghazanfari, Roshanak; Li, Hongzhe; Lim, Hooi Ching; Scheding, Stefan
• Is Part Of: European journal of haematology. Volume 101:Number 1(2018)
• Page Start: 57
• Page End: 67
• Publication Date: 2018-04-30
• Subjects: bone marrow -- JAK2 inhibition -- mesenchymal stromal cells -- myeloproliferative neoplasm -- ruxolitinib; Hematology -- Periodicals; Blood -- Diseases -- Periodicals; Blood -- Periodicals; 616.15005
• DOI: 10.1111/ejh.13079
• Languages: English
• ISSNs: 0902-4441

Abstract

Abstract: Objective: Philadelphia‐negative myeloproliferative neoplasms (MPNs) commonly share hyperactive JAK‐STAT signaling affecting hematopoietic stem cells (HSC) and their progeny. The JAK1/2 inhibitor Ruxolitinib has remarkable clinical efficacy, including spleen reduction, improvement of constitutional symptoms, and bone marrow (BM) fibrosis reversal. Whether this is due to inhibition of JAK2‐mutated HSC only, or whether Ruxolitinib also affects BM stroma is not known. Methods: This study investigated potential effects of Ruxolitinib on BM mesenchymal stromal cells (MSC), which are not only major regulators of hematopoiesis but also contribute to fibrosis, from 10 healthy donors and 7 JAK2 V617F ‐positive MPN patients. Results: Ruxolitinib moderately inhibited the growth of healthy donor MSC (HD‐MSC) and MSC from JAK2 V617F+ MPN patients (P‐MSC) in short‐ and long‐term assays. The clonogenic potential of HD‐MSC was not affected by Ruxolitinib. JAK‐STAT signaling, however, was markedly inhibited in both HD‐MSC and P‐MSC, the latter of which showed higher expression of fibrosis‐associated and hematopoiesis‐maintenance genes. Moreover, Ruxolitinib reduced MSC secretion of MCP‐1 and IL‐6. Conclusion: Ruxolitinib affected JAK2 signaling in MSC at clinically relevant doses, which is likely to contribute to the normalization of the inflammatory milieu in MPNs. Thus, combined HSC and stroma‐directed interventions have the potential to improve constitutional symptoms and reduce stromal proliferation in MPNs.