Role of CALR mutants in MPN oncogenesis delineated
Mutations in calreticulins (CALRs) play an important role in the development of myeloproliferative neoplasms (MPNs) via activation of the thrombopoietin receptor (TpoR) and JAK2 signaling. However, the exact mechanism is still unclear.
Using biochemical approaches Dr Christian Pecquet (Ludwig Institute for Cancer Research Ltd, Brussels, Belgium) and colleagues demonstrated that the signal sequence of mutant CALR is required for activation of TpoR. Interaction with mutant CALR significantly increased the thermal stability of TpoR, and resulted in translocation of the complex to the cell surface.
Moreover, the investigators provided genetic evidence that the cell-surface TpoR-CALR mutant complexes are obligatory for hematopoietic cell transformation. Mutant CALR and TpoR co-localized in the Golgi apparatus, part of the secretory pathway, and passing through this compartment was required for oncogenic transformation.
In congenital amegakaryocytic thrombocytopenia (CAMT) a mutant form of TpoR is defective in cell-surface localization and activation, which can be rescued by mutant CALR, but not wild type CALR. Cell-surface localization of mutant CALR was found to be essential for transformation. In addition, the investigators observed secretion of mutant CALR.
“We show that mutant CALRs act as rogue chaperones, leading to folding and cell-surface localization of TpoR, which is obligatory for hematopoietic cell transformation”, concluded Pecquet. “Cell surface localization of CALR mutants raises the possibility to develop immunotherapeutic strategies targeting this molecule for MPN.”