PPARγ agonists promote the resolution of myelofibrosis in preclinical models
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
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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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 2

Treatment with PPARγ agonists reduces myeloproliferation in PV-JAK2V617F and ET-CALRdel52 mice.

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Treatment with PPARγ agonists reduces myeloproliferation in PV-JAK2V617F...
(A and B) Pioglitazone decreases the hematocrit of the PV-JAK2V617F-GFP mice (A) and the platelet count of ET-CALRdel52 mice (B). (C and E) Pioglitazone reduces the proportion of the malignant JAK2V617F-GFP clone in the hematopoietic (CD45.2) cells of peripheral blood (C), especially in myeloid (CD11b) cells (E). (D and F) Pioglitazone limits expansion of the malignant CALRdel52-GFP clone in the hematopoietic (CD45.2) cells of peripheral blood (D), and the effect is greater in myeloid (CD11b) cells (F). The black vertical dashed lines indicate initiation of treatment. The horizontal lines represent the mean. *Statistically significant difference (P < 0.05). (n = 10 mice per condition, except CALR-WT pioglitazone n = 5.)