ROLE OF PPAR-Y IN HEMATOPOIESIS AND THE BONE MARROW ENVIRONMENT: PRECLINICAL MODELS AND TESTS (MPN)

Functional studies

Targeted therapy
Alternative therapy

Basic research (TRL 1-3)

Study of the mechanisms of PPAR-Y nuclear receptor activity in hematopoietic stem cells and their microenvironment.

A joint research team of CEA researchers and university hospital staff, addressing both fundamental and clinical aspects of the theme.

Description

Scope of research activities

Basic research to study the function of PPAR-Y in hematopoiesis and bone marrow stroma.

Conduct of studies

Steps :

Definition of hypothesis and study design
Drafting of study plans
Creation and validation of "in vitro" and " in vivo" models required to address the hypotheses.
Conducting the study
Analysis and results communication

Research infrastructure

Experimental and analytical platforms:

Flow cytometry
Molecular biology
Biological safety levels 2 and 3 laboratories
Small animal imaging
Animal facility

Models:

Culture of hematopoietic or bone marrow stromal cell lines
Patient primary cell cultures (hematopoietic or bone marrow stromal)
In vitro (CRISPR/Cas9) or ex-vivo (shRNA) PPARy invalidation models on cell lines.
Mouse model of PPARy invalidation in medullary stromal cells expressing the leptin receptor (C57BL/6 (B6.129(Cg)-Leprtm2(cre)Rck/J (008320) _ B6.129-Ppargtm2Rev/J (004584)).

Technical personnel:

Animaliance company staff for animal facility management
Anatomopathology platform

Specifications

The approach

Development of "in vitro" and "in vivo" models and assays for the evaluation of drug candidates for the management of myeloproliferative neoplasia (MPN) and acute myeloid leukemia (AML). Study of the therapeutic potential of PPAR-y receptor activation in these hematological disorders.

The studies

Study of drug candidates on myeloproliferation and leukemia cell persistence in MPNs and AML.:

Evaluation of the use of PPAR-y agonists as therapeutic candidates in the management of MPNs. In vitro approach in cell lines, ex vivo approach in patient cells and in preclinical mouse models of MPNs (JAK2 V617F, CALRdel52, TPOhigh). In vitro and ex-vivo viability, proliferation and clonogenicity tests (CFC; LTC-IC). Analysis of proliferating or quiescent populations (CFSE), screening of therapeutic candidates. In vivo monitoring of the hematological compartment (normal and/or pathological, treated or untreated) by blood count and flow cytometry. End-point anatomopathological analyses.

Study of the impact of medullary stromal pre-fibrosis/fibrosis in the natural history of myeloid hemopathies:

Analysis and characterization of the role of PPARy in bone marrow mesenchymal stromal cells. Effect on 1) hematopoietic support, 2) homing of hematopoietic cells, 3) susceptibility to the development of bone marrow fibrosis, 4) establishment/non-resorption of an inflammatory syndrome.

Examples of partnerships

ACTIM study (NCT02888964) - A phase II study to evaluate the efficacy and safety of pioglitazone (ACTOS®) as add-on therapy to imatinib mesylate (GLEEVEC®) in chronic phase, chronic myelogenous leukemia patients (CP-CML) in major molecular response (MMR).

Partner: Partnership with CHV de Versailles (PI: Prof. Philippe Rousselot), associated biological study (UMR-1184) (clonogenic tests and STAT5 factor expression).

Study of the therapeutic potential of PPARgamma nuclear receptor activation in myelofibrosis - Evaluation of a treatment using PPARg agonists in the management of myelofibrosis (in vitro, ex vivo and in preclinical mouse models of the disease).

Partners: UMR 1287; CIC 1427

Terms

Research partnership

OPALE entity

IDMIT (UMR-1184)

Contact

Other offers

MODELS FOR PRECLINICAL STUDIES OF THE IMPACT OF BONE MARROW FIBROSIS ON THE NATURAL HISTORY OF HEMOPATHIES (MPN)

CLINICAL TRIALS CENTER FOR THE DESIGN, SPONSORING AND CONDUCT OF PHASE I TO IV INTERVENTIONAL AND NON-INTERVENTIONAL CLINICAL TRIALS IN LEUKEMIA (CML, AML, ALL)