Modulation of human thrombopoietin receptor conformations uncouples JAK2 V617F-driven activation from cytokine-induced stimulation.

The thrombopoietin receptor (TpoR) plays a central role in myeloproliferative neoplasms (MPNs). Mutations in JAK2, calreticulin, or TpoR itself drive the constitutive activation of TpoR and uncontrolled proliferation and differentiation of hematopoietic stem cells and progenitors. The JAK2 V617F mutation is responsible for most MPNs, and all driver mutants induce pathologic TpoR activation. Existing therapeutic strategies have focused on JAK2 kinase inhibitors that are unable to differentiate between the mutated MPN clone and healthy cells. Surprisingly, the targeting of TpoR itself has remained poorly explored despite its central role in pathology. Here, we performed a comprehensive characterization of human TpoR activation under physiological and pathological conditions, focusing on the JAK2 V617F mutant. Using a system of controlled dimerization of the transmembrane and cytosolic domains of TpoR, we discovered that human TpoR (hTpoR) adopts different dimeric conformations upon Tpo-induced vs JAK2 V617F-mediated activation. We identified the amino acids and specific dimeric conformation of hTpoR responsible for activation in complex with JAK2 V617F and confirmed our findings in the full-length receptor context in hematopoietic cell lines and primary bone marrow cells. Remarkably, we found that the modulation of hTpoR conformations by point mutations allowed for specific inhibition of JAK2 V617F-driven activation without affecting Tpo-induced signaling. Our results demonstrate that modulation of the hTpoR conformation is a viable therapeutic strategy for JAK2 V617F-positive MPNs and set the path for novel drug development by identifying precise residues of hTpoR involved in JAK2 V617F-specific activation

The CMS barrel calorimeter response to particle beams from 2 to 350 GeV/c

The response of the CMS barrel calorimeter (electromagnetic plus hadronic) to hadrons, electrons and muons over a wide momentum range from 2 to 350 GeV/c has been measured. To our knowledge, this is the widest range of momenta in which any calorimeter system has been studied. These tests, carried out at the H2 beam-line at CERN, provide a wealth of information, especially at low energies. The analysis of the differences in calorimeter response to charged pions, kaons, protons and antiprotons and a detailed discussion of the underlying phenomena are presented. We also show techniques that apply corrections to the signals from the considerably different electromagnetic (EB) and hadronic (HB) barrel calorimeters in reconstructing the energies of hadrons. Above 5 GeV/c, these corrections improve the energy resolution of the combined system where the stochastic term equals 84.7±1.6% and the constant term is 7.4±0.8%. The corrected mean response remains constant within 1.3% rms