Key Points Mutant CALR induces TPO-independent growth in the human megakaryocytic cell line UT-7/TPO. Mutant CALR binds to the TPO receptor, inducing phosphorylation of JAK2 and activating downstream signaling.

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Studies have previously shown that mutant calreticulin (CALR), found in a subset of patients with myeloproliferative neoplasms (MPNs), interacts with and subsequently promotes the activation of the thrombopoietin receptor (MPL). However, the molecular mechanism behind the activity of mutant CALR remains unknown. Here we show that mutant, but not wild-type, CALR interacts to form a homomultimeric complex. This intermolecular interaction among mutant CALR proteins depends on their carboxyl-terminal domain, which is generated by a unique frameshift mutation found in patients with MPN. With a competition assay, we demonstrated that the formation of mutant CALR homomultimers is required for the binding and activation of MPL. Since association with MPL is required for the oncogenicity of mutant CALR, we propose a model in which the constitutive activation of the MPL downstream pathway by mutant CALR multimers induces the development of MPN. This study provides a potential novel therapeutic strategy against mutant CALR-dependent tumorigenesis via targeting the intermolecular interaction among mutant CALR proteins.

The complex strain-optical ratio, O*(ω), and the complex Young's modulus, E*(ω), of four vinyl polymers, atactic polypropylene, 1,2-polybutadiene, poly(ethylethylene), and poly(4-vinylbiphenyl), were measured from the rubbery plateau to the glassy zone to investigate the origin of the birefringence and the chain orientation in the glassy zone. The data, including those for polystyrene and poly(vinyl naphthalene), were analyzed through a modified stress-optical rule:  The rule states that O*(ω) and E*(ω) are described as a sum of two component functions (denoted by R and G) and that a proportional rule similar to the ordinary stress-optical rule holds well for each of the R and G components with different stress-optical coefficients. The R and G components have been interpreted to be respectively related to the orientation of the main chain axis toward the stretch direction and tilting of the structural units by a rotational orientation about the main chain axis. According to this interpretation, the stress-optical coefficients for the R and G components are predicted to decrease and increase, respectively, with increasing size of the side chain. The present study shows the validity of this prediction. In addition, it is suggested that the degree of the rotational orientation responsible for the G component becomes larger with increasing size of the side chain.