5th de Duve Lecture: Watch the podcast!
Pascale Cossart enlightens us on the molecular and cellular bases of bacterial infections.
The thrombopoietin receptor (TpoR) is the master regulator of platelet production and of hematopoietic stem cells quiescence, proliferation, and differentiation. Its activation is often dysregulated in blood diseases such as myeloproliferative neoplasms (MPNs).
The primary mutation responsible for MPNs is found in another protein, Janus kinase 2 (JAK2), a tyrosine kinase which binds to TpoR and physiologically enables the transmission of the signal induced by TpoR's natural ligand, the thrombopoietin. Under normal circumstances, this signaling occurs only when thrombopoietin induces the dimerization of two TpoR molecules and their associated JAK2. However, when the JAK2 V617F mutation is present inside the cell, it induces TpoR dimerization independently of Tpo, leading to constitutive activation of downstream signaling pathways and thus uncontrolled proliferation of blood cells.
Current treatment strategies nonspecifically inhibit both healthy and mutated JAK2, as well as other types of kinases of the JAK family, causing deleterious side effects including cancer and immune disorders. In addition, such non-specific inhibitors do not have curative potential as they do not specifically target the malignant cells.
In their study, Papadopoulos and colleagues, from the group of Pr. Stefan Constantinescu, discovered that TpoR adopts different conformations or "different shapes" when activated by its natural ligand and by mutant JAK2. After delineating the conformations adopted by TpoR in physiological versus pathological conditions, the authors devised ways to block the mutant signalling without affecting the physiological activation. This allowed specific inhibition of pathologic signaling in hematopoietic cell lines and primary bone marrow cells.
This study, published in the journal Blood, paves the way for more precise treatments aimed at modulating and specifically targeting cells carrying the mutation. These treatments could involve, for example, so-called "conformational" antibodies (which recognize a specific shape) or small molecules that would target TpoR only when coupled to mutant JAK2. Such treatments would not only allow for specific targeting with minimal or no side effects but also potentially provide a definitive cure for the disease.
Article describing this research
Papadopoulos N, Pristavec A, Nédélec A, Levy G, Staerk J, Constantinescu SN
Blood 2023, 142(21):1818–1830