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Mechanisms by which mutant CALR drives myeloproliferative neoplasms

Stefan Constantinescu, Ludwig Cancer Research
Stefan Constantinescu

Frameshift mutations in the calreticulin (CALR) protein can cause slow-growing blood cancers known as myeloproliferative neoplasms (MPNs). Such mutations induce the stable binding of CALR to the thrombopoietin receptor (TpoR) within the same cell, which constitutively activates TpoR signaling, driving cell proliferation. In an April paper in Nature Communications, researchers led by Ludwig’s Stefan Constantinescu reported the basis of the acquired specificity of CALR mutants for TpoR, how their binding triggers TpoR activation and how the complex might be targeted by drugs to treat CALR-mutant MPNs, which account for some 25% of
essential thrombocythemia and myelofibrosis cases. Another study led by Stefan and published in the journal Blood in February reported that the mutant CALR binds and is secreted into the plasma in complex with soluble transferrin receptor 1 (sTFR1), which stabilizes it and extends its half-life. The complex, Stefan and his colleagues showed, can activate TpoR much like a rogue cytokine and can generate colonies in culture in the absence of thrombopoietin. They also found that TpoR-expressing cells with a CALR mutation are uniquely sensitive to the levels of circulating mutant CALR proteins seen in patients.

Oncogenic CALR mutant C-terminus mediates dual binding to the thrombopoietin receptor triggering complex dimerization and activation
Nature Communications, 2023 April 5

Secreted mutant calreticulins as rogue cytokines in myeloproliferative neoplasms
Blood, 2023 February 23

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