Mechanism underlying the development of myeloproliferative neoplasms through mutant calreticulin

Abstract

Deregulation of cytokine signaling is frequently associated with various pathological conditions, including malignancies. In patients with myeloproliferative neoplasms (MPNs), recurrent somatic mutations in the calreticulin (CALR) gene, which encodes a molecular chaperone that resides in the endoplasmic reticulum, have been reported. Studies have defined mutant CALR as an oncogene promoting the development of MPN, and deciphered a novel molecular mechanism by which mutant CALR constitutively activates thrombopoietin receptor MPL and its downstream molecules to induce cellular transformation. The mechanism of interaction and activation of MPL by mutant CALR is unique, not only due to the latter forming a homomultimeric complex through a novel mutant‐specific sequence generated by frameshift mutation, but also for its ability to interact with immature asparagine‐linked glycan for eventual engagement with immature MPL in the endoplasmic reticulum. The complex formed between mutant CALR and MPL is then transported to the cell surface, where it induces constitutive activation of downstream kinase JAK2 bound to MPL. Refined structural and cell biological studies can provide an in‐depth understanding of this unusual mechanism of receptor activation by a mutant molecular chaperone. Mutant CALR is also involved in modulation of the immune response, transcription, and intracellular homeostasis, which could contribute to the development of MPN. In the present article, we comprehensively review the current understanding of the underlying molecular mechanisms for mutant molecular chaperone‐induced cellular transformation.

JAK and STAT gene mutations and JAK-STAT pathway activation in lympho- and myeloproliferative neoplasms

“…Presently, the mechanism of aberrant JAK-STAT pathway activation in these cases has been described. It postulates the formation of the CALRmut-MPL protein complex already within the ER, with the subsequent placement of the complex in the cell membrane of the precursor cells already in the form with the originally activated MPL receptor [120]. The proposed mechanism for activating the JAK-STAT pathway was confirmed by laboratory tests.…”

Calreticulin: Endoplasmic reticulum Ca2+ gatekeeper

“…Furthermore, calreticulin mutants secreted from malignant cells inhibit phagocytosis of dying cancer cells by dendritic cells resulting in immunosuppressive effects 122 . Importantly, the frameshift mutations of calreticulin render the C‐terminus of the protein with positively charged, affecting the Ca 2+ capacity to the protein 115 . Comparison of CALRdel52 to CALRins5 (Figure 3) indicates that while CALRdel52 has all the negative charges of the calreticulin C‐terminus converted to positive charges, there is only a ~ 50% change in charge in the CALRins5 variant 94,95,112 .…”

A Chaperone-Like Role for EBI3 in Collaboration With Calnexin Under Inflammatory Conditions

“…This is attributed to constitutive activation of the thrombopoietin receptor, myeloproliferative leukemia protein (MPL), by the mutant calreticulin, resulting in transformation. Surprisingly, the underlying mechanism is so unique that it is currently considered to be due to initial formation of a dimeric or homomultimeric complex of the mutant calreticulin via a novel mutant-specific sequence generated by frameshift mutation, and subsequent interaction with immature asparagine-linked glycan for eventual engagement with immature MPL in the ER (73,74). The complex formed between mutant calreticulin and MPL is then transported to the cell surface, where it induces constitutive activation of the downstream JAK2/STAT5 signaling pathway in an MPL-dependent manner.…”