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Mutations of the calreticulin gene (CALR) have been recognized as driver mutations involved in the development of myeloproliferative neoplasms (MPN) along with Janus kinase (JAK) or thrombopoietin receptor (MPL) mutations. CALR mutations in MPN are insertion-deletion mutations, and the most common is a 52-bp deletion (CALRdel52).
CALRdel52 homomultimers are responsible for binding to MPL and causing constitutive activation of JAK-STAT signaling. However, there is limited understanding of the mechanism of CALRdel52 interaction with MPL and its activation.
Rivera et al. recently conducted a comprehensive mutagenesis analysis and explored the mechanism of CALRdel52 binding and activation of the MPL signal, including the role of the glycan-binding lectin motif, which associates with the extracellular domain of MPL and the zinc-binding domain.1 The results are published in Blood Advances, and the MPN Hub is pleased to summarize the key findings here.
293T cells were derived from the American Type Culture Collection, and MPL-expressing Ba/F3 cells were generated by retroviral transduction. Peripheral blood mononuclear cells were isolated from patients with MPN.
Residues related with lectin and zinc-binding activity are essential for oncogenic activity based on a mutagenesis screen described below:
Histidine-mutated CALRdel52 is incapable of homomultimerization:
Zinc is essential for CALRdel52-MPL complex formation and downstream signaling:
TPEN preferentially eradicates CALR-mutant primary MPN cells:
This study provides a better understanding of the molecular mechanism through which CALRdel52 exerts its oncogenic activity. The study identifies the zinc-binding histidines within CALRdel52 essential for the formation of homomultimers that interact with MPL to induce its constitutive activation. It also shows that homomultimerization and the MPL-binding of CALRdel52 are zinc-dependent and could therefore, be a potential target for treatment of CALR-mutant MPNs.
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