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

Zacharaki, Dimitra LU ; Ghazanfari, Roshanak LU ; Li, Hongzhe LU ; Lim, Hooi Ching LU and Scheding, Stefan LU (2018) In European Journal of Haematology 101(1). p.57-67
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:... (More)

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.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
bone marrow, JAK2 inhibition, mesenchymal stromal cells, myeloproliferative neoplasm, ruxolitinib
in
European Journal of Haematology
volume
101
issue
1
pages
11 pages
publisher
Wiley-Blackwell
external identifiers
  • scopus:85048895780
ISSN
0902-4441
DOI
10.1111/ejh.13079
language
English
LU publication?
yes
id
814176f2-111a-4767-a46e-2b4635d28e6f
date added to LUP
2018-07-04 12:57:06
date last changed
2019-10-15 06:41:19
@article{814176f2-111a-4767-a46e-2b4635d28e6f,
  abstract     = {<p>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<sup>V617F</sup>-positive MPN patients. Results: Ruxolitinib moderately inhibited the growth of healthy donor MSC (HD-MSC) and MSC from JAK2<sup>V617F+</sup> 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.</p>},
  author       = {Zacharaki, Dimitra and Ghazanfari, Roshanak and Li, Hongzhe and Lim, Hooi Ching and Scheding, Stefan},
  issn         = {0902-4441},
  keyword      = {bone marrow,JAK2 inhibition,mesenchymal stromal cells,myeloproliferative neoplasm,ruxolitinib},
  language     = {eng},
  month        = {07},
  number       = {1},
  pages        = {57--67},
  publisher    = {Wiley-Blackwell},
  series       = {European Journal of Haematology},
  title        = {Effects of JAK1/2 inhibition on bone marrow stromal cells of myeloproliferative neoplasm (MPN) patients and healthy individuals},
  url          = {http://dx.doi.org/10.1111/ejh.13079},
  volume       = {101},
  year         = {2018},
}