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Effects of JAK 1/2 inhibition on bone marrow stromal cells of myeloproliferative neoplasm ( MPN ) patients and healthy individuals
Author(s) -
Zacharaki Dimitra,
Ghazanfari Roshanak,
Li Hongzhe,
Lim Hooi Ching,
Scheding Stefan
Publication year - 2018
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.13079
Subject(s) - ruxolitinib , myelofibrosis , myeloproliferative neoplasm , bone marrow , stromal cell , haematopoiesis , medicine , cancer research , extramedullary hematopoiesis , mesenchymal stem cell , fibrosis , stem cell , biology , pathology , microbiology and biotechnology
Objective Philadelphia‐negative myeloproliferative neoplasms ( MPN s) commonly share hyperactive JAK ‐ STAT signaling affecting hematopoietic stem cells ( HSC ) and their progeny. The JAK 1/2 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 JAK 2‐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 JAK 2 V617F ‐positive MPN patients. Results Ruxolitinib moderately inhibited the growth of healthy donor MSC ( HD ‐ MSC ) and MSC from JAK 2 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 JAK 2 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 MPN s.