The identification that the thrombopoietin receptor adopts different conformations when it is attached to wild-type JAK2 (left) or to the mutant JAK2 V617F (middle). This may allow the development of novel specific therapies (right) that would prevent the pathologic conformation induced by JAK2 V617F.
Formation of blood requires small circulating proteins, called cytokines, such as erythropoietin, or thrombopoietin that induce survival, growth and differentiation of blood precursors. They bind to receptors on target cells, which function like ‘antennae’ that transmit a signal to the cell interior. We study how these specific receptors assemble on the cell membrane and couple at the cell interior to JAKs, which are absolutely required to transmit a signal. We found that mutations in JAKs or in receptors themselves or in proteins that can activate receptors (such as the chaperone calreticulin) confuse the cells and make them grow indefinitely, leading to blood cancers, specifically myeloproliferative neoplasms (MPNs). A curative treatment needs mutant-specific inhibitors. We found that the conformation of receptors or JAK2 mutants differ from physiologic receptor-JAK2 complexes, which may allow targeted inhibition (Figure). We study how signaling mutations impact epigenetic regulators and how MPNs progress to acute myeloid leukemia. We also study leukemia in children, especially those being resistant to treatment. This work is supported by ‘Les avions de Sébastien’.
In order to pursue our aims, we use molecular, biophysical approaches, like deuterium exchange mass spectrometry as well as in vivo transgenesis, mouse bone marrow transplantation, as well as investigation of primary patient cells.