Principal investigator: FRANÇOIS DELHOMMEAU

Dynamic crosstalks in the development of acute myeloid leukemias in their ecosystem

The four teams of EcoAML networks are focused on Acute Myeloid Leukemia (AML). During the development of this liquid tumor originating from bone marrow (BM), Hematopoietic Stem and Progenitor Cells (HSPCs) and their BM ecosystem may undergo multiple changes. The network hypothesizes that pre-leukemic HSPCs alter their surrounding environment and particularly mesenchymal stroma cells (MSCs). The aims of the project are to decipher and model the mechanisms of the crosstalk between normal, pre-leukemic, leukemic HSPCs and MSCs to further identify new targets to eradicate the malignant clone in AML - Add Text.

Proof of concept and model the crosstalk between HSPCs engineered to mimic pre-leukemic lesions and surrogate MSC cell lines

The network works on the proof of concept and modeling of the crosstalk between HSPCs engineered to mimic pre-leukemic lesions (often TET2/DNMT3A mutations) and surrogate MSC cell lines. The experimental design consists in placing the niche cells in contact with hematopoietic cells for a few days without cytokines/growth factors. Cells are collected at the end of the culture, FACS-sorted based on hematopoietic vs non-hematopoietic surface markers and prepared for transcriptome analysis. This short co-culture period was shown to be sufficient to establish robust niche cell/HSPC interactions and to even identify time course changes in transcriptome.

Multi-scales analysis of the crosstalk between primary HSPCs and MSCs from AML and healthy bone marrow samples

EcoAML also studies and models at the genome wide scale the crosstalk between primary HSPCs and MSCs from AML and healthy bone marrow samples. Analyses are performed on three group of patients carrying, I) TET2 mutation, II) DNMT3A mutation and III) without the aforementioned mutations. This two first tasks will provide a multi-scale (mRNA, miRNA and lncRNA) analysis of molecular pathways controlling hematopoietic-stromal cell relationships. Essential hubs in gene regulatory networks will be identified

Gain and loss of function of prioritized genes/pathways studies

Finally, the network works to validate data and models by focusing on the most relevant candidate pathways/genes/non-coding transcripts identified. Antagonists or agonists of the molecular targets should constitute novel and original pharmacological compounds in regenerative medicine. EcoAML focus on the analysis of mRNA and the proteins they encode, and particularly on factors implicated in HSPC self-renewal/amplification. Prioritized candidates are subjected to gain and loss of function in vitro and in vivo studies. The teams work with lentiviruses to force or to prevent (shRNA) the expression of the candidate genes.

Understanding and modelling the crosstalk between these cell populations at time of disease initiation or evolution will help identifying new therapeutic tools against AML. Many of the results, will be available as an open resource, and will be useful to devise new procedures for the treatment of diseased HSPCs. This in-depth analysis will reveal potential mRNA, miRNA and lncRNA as candidates to participate in the regulation of normal vs leukemic HSPC through the normal vs leukemic niche

This French program is organized by ITMO Cancer, in collaboration with ITMO BCDE (Cell Biology, Development and Evolution) and ITMO Technologies for Health of the National Alliance for Life Sciences and Health (AVIESAN) with the National Cancer Institute (INCA) and Inserm within the framework of the Cancer Plan. Operational management is entrusted to Inserm.
It was launch in order to develop a critical mass of resources and skills in order to conduct interdisciplinary research projects in the field of functional heterogeneity of cellular tumor relations in their ecosystem: the "HTE Program".

Initiation of HTE Program