Effects of calreticulin mutations on HLA class I expression in myeloproliferative neoplasms

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Abstract

Essential thrombocythemia (ET) and myelofibrosis (MF) are myeloproliferative neoplasms (MPN) that can result from heterozygous or homozygous mutations in the calreticulin (CRT) gene (CALR). Mutant CRT binds to the thrombopoietin receptor to induce signaling that drives ET and MF. CRT is also a chaperone for the assembly of the highly polymorphic human leukocyte antigen (HLA) class I molecules. The effects of heterozygous versus homozygous MPN CALR mutations on the expression of HLA class I variants are unknown. To assess mutant CRT-induced changes to HLA class I expression, we generated CRISPR-based mutant CALR knock-in cell lines and CALR-knockout cell lines reconstituted with wild-type or MPN mutant CALR and also undertook measurements in MPN patient platelets and monocytes. Collectively, our findings indicate that heterozygous CALR mutations preserve HLA class I surface expression, whereas full loss of wild-type CRT results in marked, allele-dependent reductions in HLA class I expression, which are rescued by wild-type CRT but not MPN mutants. Reduced expression of CRT-dependent HLA class I in cells lacking a functional CRT induces natural killer (NK) cell activation. These studies identify specific HLA class I alleles and homozygous CALR mutations as prerequisites for low HLA class I expression in MPN.

Authors

Amanpreet Kaur, Grace Pagnucco, Fawziyah S. Khatri, Harini Desikan, Malathi Kandarpa, Matthew Cusick, Moshe Talpaz, Malini Raghavan