Effects of calreticulin mutations on HLA class I expression in myeloproliferative neoplasms 3478

Description Human Leukocyte Antigen (HLA) class I molecules present peptide antigens to CD8+ T cells and regulate the activities of natural killer (NK) cells. A subset of patients with Myeloproliferative Neoplasms (MPNs) have somatic mutations in calreticulin, a key chaperone for HLA class I assembly. Typically, MPN mutations occur in a heterozygous context with a wild type calreticulin allele. Analysis of individual HLA class I allotypes reveals strong allele-specific effects of full calreticulin deficiency on surface HLA class I expression, and MPN mutants fail to restore expression for all tested allotypes. Notably, for even the most calreticulin-dependent HLA class I allotypes, only small reductions are measured when the MPN calreticulin mutants are expressed in a heterozygous context with wild type calreticulin. Correspondingly, surface HLA class I expression in peripheral blood cells from MPN patients with calreticulin mutations falls within the normal range, with higher expression measured in patients treated with interferon-a. Furthermore, NK cells from MPN patients with calreticulin mutations are not intrinsically activated. Overall, these findings indicate small effects on HLA class I expression of heterozygously expressed MPN calreticulin mutations, relevant to the majority of MPN patients with these mutations. Thus, targeted immunotherapy using checkpoint inhibitors and vaccines against selected MPN epitopes can be used to enhance MPN-specific immunity. Funding Sources Supported by NIH grant (R01 AI123957)