MPNs lacking those specific driver mutations are commonly called ‘triple negatives’, which amount to 15% of ET and PMF and appear to share with phenotypic drivers the ability to activate the JAK/STAT pathway. 1 Beside JAK2 and STATs, MPL/TpoR is a central player in the pathogenesis of MPN being essential for developing a full JAK2 V617F disease in mice. 2 However, the receptor itself can suffer from pathological activating mutations within exon10. Exon10 covers roughly the transmembrane domain (TMD) of TpoR and starts at Trp491 (exoplasmic TMD boundary) to end shortly after Trp515 (cytosolic TMD boundary). Those two tryptophans are predicted to be on the same face of the TMD helix and are capping the TMD helix in the membrane bilayer. Trp515 is found in an amphipathic and helical motif ‘RWQFP’that prevents activation of TpoR. 3 Trp515 itself controls dimerization and activation of the receptor. 4 W515S, 5 W515L, 6 W515K, 7 W515A, 8 W515R9 and W515G10 were shown to be present in a subset of MPN patients (nearby 4% ET and 8% PMF in large cohorts), or in autonomous cell lines but have never been found in polycythemia vera or other myeloid diseases. 7, 11, 12 W515L/K mutations are the most prevalent mutations that activate the receptor and recapitulate an ET/PMF phenotype with marked thrombocytosis in murine bone marrow transplant assays. 6, 8 Besides missense mutations, rare deletions and insertions around W515 are found in MPN patients. 10, 12