Signaling, Hematopoiesis and Mechanism of Oncogenesis

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.

The team

From left to right J Agopian, É Lecocq, S Letard, N Coppet, MT Borrello, P De Sepulveda, A Legrand, F Brenet, K Hanssens, S Lopez, P Dubreuil, E Soucie, Y Forand.