DS04 - Vie, santé et bien-être

Impact of nuclear receptor PPARy in normal and pathological hematopoiesis – HemaPpar

Submission summary

The peroxisome proliferator-activated receptor-gamma (PPARy) is a protein of the nuclear receptor superfamily which naturally binds lipids and acts as a transcription factor. Initially described as the "master" gene of adipogenesis, PPARy activation also potentiates the action of insulin, justifying the use of a family of its synthetic ligands, thiazolidinedione (TZD), in the treatment of type II diabetes. While these two properties have been the subject of intense research, the scope of PPARy receptor is today significantly expanded, including a role in controlling metabolism and inflammatory processes.
We previously reported the involvement of PPARy in the regulation of hematopoiesis and more particularly its role in the governance of the balance between quiescence and / or proliferation of hematopoietic stem cells (HSC)1. More recently, we have been able to show, through the example of chronic myeloid leukemia (CML), the therapeutic potential of PPARy ligands in the elimination of leukemic stem cells (CSL) resistant to conventional treatments, both in vitro2 and in a phase 2 clinical trial3. Since the natural ligands of PPARy, free fatty acids, prostaglandin J2, leukotriene B4 are able of maintaining residual activation of the receptor4 and that the activation of PPARy affects the compartment of CSH1,2, we propose to explore the effect of antagonists and / or invalidation of the PPARy gene as a tool for amplification of the HSC compartment. However, hematopoiesis regulation is a complex phenomenon, involving mechanistic intrinsic to hematopoietic cells, but also extrinsic factors that can be cellular trough the medullary stroma, or cytokinic with in part the inflammatory proteins5. Medullary fibrosis (myelofibrosis) is an illustration of these interactions. Indeed, in this pathology, the proliferation of blood cells6 is associated with the installation of a pro-inflammatory context7 responsible for a remodeling of the medullary stroma8 which in turn, leads to an alteration of the hematopoiesis. Although nothing has been reported in the bone marrow, PPARy's abilities to prevent fibrosis have been described in hepatic9, renal10, intestinal11 or skin12 tissues. Similarly, the use of PPARy ligands (sulfasalazine, mesalazine) is already recommended for the management of chronic inflammatory diseases (ulcerative colitis, Crohn's disease or rheumatoid arthritis)13. Myelofibrosis appears to be an excellent model for studying the involvement of PPARy in hematopoiesis. Moreover, through its simultaneous putative action on haematopoietic cell proliferation, inflammation regulation and stromal fibrosis, PPARy appears as an interesting therapeutic candidate in the management of medullary fibrosis.
The mechanisms underlying the activity of PPARy in stem cells and in their microenvironment as well as the divergences between the physiological and pathological context remain now to be characterized further. A better knowledge of the signaling pathways underlying PPAR? is necessary to understand and evaluate the potential of targeting PPARy in key areas such as 1) expansion of the CSH compartment, 2) Positive selection of genetically modified cells, 3) persistence and resistance of CSLs, 4) alterations of the medullary stroma, 5) inflammatory response.
In addition to its fundamental aspects, this project involving in vitro, in vivo (murine models) and ex-vivo (patient cells) approaches also present a therapeutic potential. If our results demonstrate the benefice of PPARy targeting in medullary fibrosis, a clinical evaluation may be considered.

Project coordination

Stephane Prost (THÉRAPIE GÉNIQUE ET CONTRÔLE DE L'EXPANSION)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CEA/STI/TGCE THÉRAPIE GÉNIQUE ET CONTRÔLE DE L'EXPANSION

Help of the ANR 299,160 euros
Beginning and duration of the scientific project: - 36 Months

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