TGF-[beta] signaling in myeloproliferative neoplasms contributes to myelofibrosis without disrupting the hematopoietic niche

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 bo...

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Bibliographic Details
Published in:The Journal of clinical investigation 2022-06, Vol.132 (11)
Main Authors: Yao, Juo-Chin, Oetjen, Karolyn A, Wang, Tianjiao, Xu, Haoliang, Abou-Ezzi, Grazia, Krambs, Joseph R, Uttarwar, Salil, Duncavage, Eric J, Link, Daniel C
Format: Article
Language:English
Subjects:
Development and progression
Genetic aspects
Health aspects
Hematopoietic stem cells
Leukemia
Lymphomas
Myelofibrosis
Myeloproliferative disorders
Physiological aspects
Transforming growth factors
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI154092