PPARγ agonists promote the resolution of myelofibrosis in preclinical models
Juliette Lambert, … , Philippe Rousselot, Stéphane Prost
Juliette Lambert, … , Philippe Rousselot, Stéphane Prost
Published April 29, 2021
Citation Information: J Clin Invest. 2021;131(11):e136713. https://doi.org/10.1172/JCI136713.
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Research Article Hematology

PPARγ agonists promote the resolution of myelofibrosis in preclinical models

Abstract

Myelofibrosis (MF) is a non–BCR-ABL myeloproliferative neoplasm associated with poor outcomes. Current treatment has little effect on the natural history of the disease. MF results from complex interactions between (a) the malignant clone, (b) an inflammatory context, and (c) remodeling of the bone marrow (BM) microenvironment. Each of these points is a potential target of PPARγ activation. Here, we demonstrated the therapeutic potential of PPARγ agonists in resolving MF in 3 mouse models. We showed that PPARγ agonists reduce myeloproliferation, modulate inflammation, and protect the BM stroma in vitro and ex vivo. Activation of PPARγ constitutes a relevant therapeutic target in MF, and our data support the possibility of using PPARγ agonists in clinical practice.

Authors

Juliette Lambert, Joseph Saliba, Carolina Calderon, Karine Sii-Felice, Mohammad Salma, Valérie Edmond, Jean-Claude Alvarez, Marc Delord, Caroline Marty, Isabelle Plo, Jean-Jacques Kiladjian, Eric Soler, William Vainchenker, Jean-Luc Villeval, Philippe Rousselot, Stéphane Prost

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Figure 5

Pioglitazone reduces induction of the TGF-β1 profibrotic target gene CTGF in a p300-dependent manner.

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Pioglitazone reduces induction of the TGF-β1 profibrotic target gene CTG...
(A–C) Pioglitazone decreases the induction of transcription of the CTGF gene induced by TGF-β1 in MS5 BM stromal cells (A), HS5 BM stromal cells (B), and primary BM stromal cells (C). (D and E) The inhibitory effect of pioglitazone is abrogated by the chemical inhibitor of the HAT activity of the p300 cofactor C646 in MS5 BM stromal cells (D) and HS5 BM stromal cells (E). (F–H) Overexpression of the efficient p300 protein (HAT+) in MS5 BM stromal cells abrogates the inhibitory effect of pioglitazone on the induction of CTGF related to TGF-β1 stimulation (G) relative to control transduction with an empty lentivirus (F), whereas overexpression of the deficient p300 protein (HAT–; H) has no effect (graphs are representative of 1 experiment). (I) Percentage of reduction in cumulative analysis (n = 4). The black horizontal lines represent the mean. *Statistically significant difference (P < 0.05). CTGF, connective tissue growth factor; HAT, histone acetyltransferase; SB, SB-431542 (inhibitor of TGF-β1 receptor).