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Effects of JAK1/2 inhibition on bone marrow stromal cells of myeloproliferative neoplasm (MPN) patients and healthy individuals.
Eur J Haematol 2018; 101(1):57-67EJ

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 JAK2V617F -positive MPN patients.

RESULTS

Ruxolitinib moderately inhibited the growth of healthy donor MSC (HD-MSC) and MSC from JAK2V617F+ 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.

Authors+Show Affiliations

Division of Molecular Hematology & Lund Stem Cell Center, Lund University, Lund, Sweden.Division of Molecular Hematology & Lund Stem Cell Center, Lund University, Lund, Sweden.Division of Molecular Hematology & Lund Stem Cell Center, Lund University, Lund, Sweden.Division of Molecular Hematology & Lund Stem Cell Center, Lund University, Lund, Sweden.Division of Molecular Hematology & Lund Stem Cell Center, Lund University, Lund, Sweden. Department of Hematology, Skåne University Hospital Lund, Lund, Sweden.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29645296

Citation

Zacharaki, Dimitra, et al. "Effects of JAK1/2 Inhibition On Bone Marrow Stromal Cells of Myeloproliferative Neoplasm (MPN) Patients and Healthy Individuals." European Journal of Haematology, vol. 101, no. 1, 2018, pp. 57-67.
Zacharaki D, Ghazanfari R, Li H, et al. Effects of JAK1/2 inhibition on bone marrow stromal cells of myeloproliferative neoplasm (MPN) patients and healthy individuals. Eur J Haematol. 2018;101(1):57-67.
Zacharaki, D., Ghazanfari, R., Li, H., Lim, H. C., & Scheding, S. (2018). Effects of JAK1/2 inhibition on bone marrow stromal cells of myeloproliferative neoplasm (MPN) patients and healthy individuals. European Journal of Haematology, 101(1), pp. 57-67. doi:10.1111/ejh.13079.
Zacharaki D, et al. Effects of JAK1/2 Inhibition On Bone Marrow Stromal Cells of Myeloproliferative Neoplasm (MPN) Patients and Healthy Individuals. Eur J Haematol. 2018;101(1):57-67. PubMed PMID: 29645296.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of JAK1/2 inhibition on bone marrow stromal cells of myeloproliferative neoplasm (MPN) patients and healthy individuals. AU - Zacharaki,Dimitra, AU - Ghazanfari,Roshanak, AU - Li,Hongzhe, AU - Lim,Hooi Ching, AU - Scheding,Stefan, Y1 - 2018/04/30/ PY - 2018/03/29/accepted PY - 2018/4/13/pubmed PY - 2018/10/12/medline PY - 2018/4/13/entrez KW - JAK2 inhibition KW - bone marrow KW - mesenchymal stromal cells KW - myeloproliferative neoplasm KW - ruxolitinib SP - 57 EP - 67 JF - European journal of haematology JO - Eur. J. Haematol. VL - 101 IS - 1 N2 - 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 JAK2V617F -positive MPN patients. RESULTS: Ruxolitinib moderately inhibited the growth of healthy donor MSC (HD-MSC) and MSC from JAK2V617F+ 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. SN - 1600-0609 UR - https://www.unboundmedicine.com/medline/citation/29645296/Effects_of_JAK1/2_inhibition_on_bone_marrow_stromal_cells_of_myeloproliferative_neoplasm__MPN__patients_and_healthy_individuals_ L2 - https://doi.org/10.1111/ejh.13079 DB - PRIME DP - Unbound Medicine ER -