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Myeloproliferative neoplasms (MPNs) are frequently driven by mutations within the C-terminal domain (C-domain) of calreticulin (CRT). CRTDel52 and CRTIns5 are recurrent mutations. Oncogenic transformation requires both mutated CRT and the thrombopoietin receptor (Mpl), but the molecular mechanism of CRT-mediated constitutive activation of Mpl is unknown. We show that the acquired C-domain of CRTDel52 mediates both Mpl binding and disulfide-linked CRTDel52 dimerization. Cysteine mutations within the novel C-domain (C400A and C404A) and the conserved N-terminal domain (N-domain; C163A) of CRTDel52 are required to reduce disulfide-mediated dimers and multimers of CRTDel52. Based on these data and published structures of CRT oligomers, we identify an N-domain dimerization interface relevant to both WT CRT and CRTDel52. Elimination of disulfide bonds and ionic interactions at both N-domain and C-domain dimerization interfaces is required to abrogate the ability of CRTDel52 to mediate cell proliferation via Mpl. Thus, MPNs exploit a natural dimerization interface of CRT combined with C-domain gain of function to achieve cell transformation. 

Abstract Throughout the Phanerozoic, estimated CO₂levels from CO₂proxies generally correlate well with independent estimates of temperature. However, some proxy estimates of atmospheric CO₂during the Late Cretaceous and early Paleocene are low (<400 ppm), seemingly at odds with elevated sea surface temperature. Here we evaluate early Paleocene CO₂by applying a leaf gas‐exchange model toPlatanitesleaves of four early Paleocene localities from the San Juan Basin, New Mexico (65.66–64.59 Ma). We first calibrate the model on two modernPlatanusspecies,Platanus occidentalisandP. × acerifolia, where we find the leaf gas‐exchange model accurately predicts present‐day CO₂, with a mean error rate between 5% and 14%. Applying the model to the early Paleocene, we find CO₂varies between ∼660 and 1,140 ppm. These estimates are consistent with more recent CO₂estimates from boron, leaf gas‐exchange, liverwort, and paleosol proxies that all suggest moderate to elevated levels of CO₂during the Late Cretaceous and early Paleocene. These levels of atmospheric CO₂are more in keeping with the elevated temperature during this period.