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TGF-[beta] signaling in myeloproliferative neoplasms contributes to myelofibrosis without disrupting the hematopoietic niche
- Source :
- Journal of Clinical Investigation. June 1, 2022, Vol. 132 Issue 11
- Publication Year :
- 2022
-
Abstract
- Myeloproliferative neoplasms (MPNs) are associated with significant alterations in the bone marrow microenvironment that include decreased expression of key niche factors and myelofibrosis. Here, we explored the contribution of TGF-[beta] to these alterations by abrogating TGF-[beta] signaling in bone marrow mesenchymal stromal cells. Loss of TGF-[beta] signaling in Osx-Cre-targeted MSCs prevented the development of myelofibrosis in both [MPL.sup.W515L] and [Jak2.sup.V617F] models of MPNs. In contrast, despite the absence of myelofibrosis, loss of TGF-[beta] signaling in mesenchymal stromal cells did not rescue the defective hematopoietic niche induced by [MPL.sup.W515L], as evidenced by decreased bone marrow cellularity, hematopoietic stem/ progenitor cell number, and Cxcl12 and Kitlg expression, and the presence of splenic extramedullary hematopoiesis. Induction of myelofibrosis by [MPL.sup.W515L] was intact in Osx-Cre [Smad4.sup.fl/fl] recipients, demonstrating that SMAD4-independent TGF-[beta] signaling mediates the myelofibrosis phenotype. Indeed, treatment with a c-Jun N-terminal kinase (JNK) inhibitor prevented the development of myelofibrosis induced by [MPL.sup.W515L]. Together, these data show that JNK-dependent TGF-[beta] signaling in mesenchymal stromal cells is responsible for the development of myelofibrosis but not hematopoietic niche disruption in MPNs, suggesting that the signals that regulate niche gene expression in bone marrow mesenchymal stromal cells are distinct from those that induce a fibrogenic program.<br />Introduction The bone marrow provides a specialized microenvironment that supports hematopoiesis. Hematopoietic niches in the bone marrow are dependent, in part, on the constitutive production of certain cytokines and chemokines [...]
- Subjects :
- Myeloproliferative disorders -- Development and progression
Leukemia -- Development and progression
Lymphomas -- Development and progression
Myelofibrosis -- Development and progression
Hematopoietic stem cells -- Genetic aspects -- Health aspects
Transforming growth factors -- Physiological aspects -- Health aspects
Health care industry
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 132
- Issue :
- 11
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.706296494
- Full Text :
- https://doi.org/10.1172/JCI154092