Myeloproliferative neoplasms (MPNs) are a group of rare blood diseases that progress throughout the life of the patient and which cause serious vascular and hematological complications.

Characterized by mutations in several genes (notably JAK2, MPL and CALR), these diseases result from complex interactions that trigger:

an initial growth phase of hematopoietic stem cells (HSCs), followed by an abnormal monoclonal expansion of these same cells, which is responsible for the proliferation and maturation of the different lineages;

• an inflammatory syndrome;
• and fibrosis of the bone marrow.

The "classic" MPNs include:

• chronic myeloid leukemia (CML);
• polycythemia vera (PV);
• essential thrombocythemia (ET);
• and primary myelofibrosis (PMF).

Myelofibrosis, whether or not it is secondary to another disease (ET or PV), is characterized by a failure in blood cell production by the bone marrow, which is progressively invaded by deposits of reticulin and collagen fibers, and is a stromal reaction due to the abnormal clonal expansion of HSCs. Myelofibrosis results in an alteration of the patient's general condition and includes weight loss, anemia and enlargement of the spleen (splenomegaly).

Patients with severe myelofibrosis have a poor prognosis with increased morbidity due to various complications (thrombosis, hemorrhaging, infections, and progression to acute leukemia) that shorten survival time to about six years. Current treatments are mainly palliative and oriented towards the improvement of symptoms, as no curative treatment exists apart from allogenic bone marrow stem cell transplantation.

Building on their previous work on the development of a therapy for chronic myeloid leukemia, researchers at CEA-Jacob chose to study the PPAR-γ/STAT-5 molecular regulatory pathway in order to identify new therapeutic approaches to slow the development of myelofibrosis.

More precisely, they selected agonists (ligands) of the nuclear receptor PPAR-γ with a Marketing Authorization Application (MAA) – pioglitazone (Actos®) for type 2 diabetes and mesalazine (Pentasa®) for pathologies involving chronic inflammation – and evaluated their action on myelofibrosis.

Tests performed in vitro on hematopoietic cell lines and ex vivo on primary cells from patients with myelofibrosis made it possible to understand the mechanisms underlying the antiproliferative action of PPAR-γ on hematopoietic progenitor cells. These analyses were then complemented with in vivo assays targeting the proliferation of myeloid lineages in three preclinical mouse models of myelofibrosis: the JAK2^V617F post-polycythemia vera model, the post-essential thrombocythemia or post-Calreticulin model (CALRdel52), and the TPO^high model.

This work shows that treatment with PPAR-γ agonists prevents the drop in hemoglobin associated with the pathology in the studied mouse models. These agonists reduce the proliferation of hematopoietic progenitors and blood cells of the myeloid lineage (notably by a decrease in STAT-5 activity), modulate inflammatory cytokines and protect the bone marrow stroma by blocking the activity of a major cytokine (TGF-β) responsible for the development of fibrosis.

By acting on the three key axes of myelofibrosis development, PPAR-γ activation constitutes a relevant therapeutic target, and these data support the possibility of using PPAR-γ agonists in clinical practice.
 
This work was carried out by a CEA-Jacob team that is part of the OPALE consortium, a Carnot Institute dedicated to R&D in the field of leukemia and related diseases.