To better understand the aging of hematopoietic stem cells through a transcriptomic approach at the single cell level -

Hematopoiesis is a perfect model of cellular differentiation to study molecular mechanisms involved in the transition between a highly regulated system leading to differentiation programs and homeostasis to deregulated situations leading to proliferative syndromes and leukaemia.

Our group contributes to the identification of mechanisms, transduction pathways and protein effectors initiated by genetic alterations affecting the c-Kit tyrosine kinase receptor. We identified these alterations in blood disorders, mastocytosis, gastrointestinal tumors and melanomas. Ultimately our goal is to generalize our strategy to study other receptors important in onco-hematology such as FLT3.

Our project is based on three main approaches in which we have a recognized expertise:

The functional identification of activating mutations in tyrosine kinase receptors. This expertise acquired in the c-Kit and mastocytosis models (inside the AFIRMM network) is the basis of collaborations with clinical groups and other research groups interested in the identification of mutations of other proteins involved in tumoral pathologies.
The identification of new substrates / new pathways associated with the c-Kit oncogenic signalling. We addressed this question by various proteomic (yeast two hybrid, mass spectrometry) and functional (siRNA kinome) approaches. Our expertise in gene transfer in hematopoietic progenitors is also an asset in our functional approach. Our goal is to identify new therapeutic targets.
A contribution in the identification of tyrosine kinase inhibitors (in collaboration with AB Science company).
We participate in the optimization of compounds used in targeted therapy. Masitinib targeting c-Kit is one of these new drugs.

Project 1 : Characterization of essential kinases involved in cell transformation

Kinases are promising therapeutic targets in cancer. While a lot of attention has focused on few well characterized oncogenes/oncoproteins, we postulate that pathologic signaling is still largely unknown and, as a consequence, a number of crucial targets which participate in cell transformation are still currently ignored.

During the last few years we have been studying two hematological disorders related to the activation of oncogenic RTK signaling. Mastocytosis is a rare chronic disease due to the acquisition of mutations in KIT receptor.  AML is the most frequent acute leukemia in adults and 30% of patients harbor an oncogenic mutation in FLT3 receptor.  Despite the available targeted therapy against KIT and FLT3, patients relapse after an initial response, therefore there is a need to alternative therapeutic targets.

We have performed screens aiming at identify original and novel essential effectors of signaling pathways downstream of the oncogenic KIT and FLT3 receptor in the context of mastocytosis and Acute Myeloid Leukemia (AML). We are currently studying several kinases identified in our screens as essential for survival or proliferation of mastocytosis or AML leukemic cells. Our goal is to transfer some of our basis science discoveries to preclinical assays.

Project 2 : Oncométabolisme dans les hémopathies malignes
Project 3 : Development and characterization of small chemical inhibitors