Effects of Calreticulin mutations on HLA Class I expression and function in Myeloproliferative Neoplasms

Pr Malini Raghavan

06 October 2026

Seminar

Pratical info

11:00 - 12:00

Room Schapira

Reduced mobility access

Abstract: Myeloproliferative neoplasms (MPN) can result from mutations in the calreticulin (CRT) gene (CALR), which encodes a chaperone important for human leukocyte antigen (HLA) class I assembly. CRISPR knock-in cell lines expressing mutant and endogenous CALR preserve or induce surface HLA class I levels in an allele-dependent manner. In contrast, cell lines lacking wild-type CRT display allele-dependent reductions in HLA class I expression, which mutant CRTs fail to rescue. Correspondingly, HLA class I expression is generally in the normal range in platelets and monocytes from myeloproliferative neoplasm (MPN) patients with heterozygous CALR mutations, whereas rare cases with homozygous CALR mutations show lower expression. Wild type CRT deficiency with or without MPN mutant expression induces NK cell activation. These studies demonstrate varying CRT dependencies of HLA class I expression, identify specific HLA class I alleles and homozygous CALR mutations as prerequisites for low HLA class I expression in MPN and illustrate the potential for inducing NK cell-mediated immunity in some patients. Furthermore, the maintenance/induction of surface HLA class I levels in cells with heterozygous CALR mutations highlights the prospect for harnessing CD8+ T cell-driven immune responses against MPN.

Bibliography

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The C-Terminal Acidic Region of Calreticulin Mediates Phosphatidylserine Binding and Apoptotic Cell Phagocytosis. Wijeyesakere SJ, Bedi SK, Huynh D, Raghavan M.J Immunol. 2016 May 1;196(9):3896-3909. doi: 10.4049/jimmunol.1502122. Epub 2016 Apr 1.

Regulation of calreticulin-major histocompatibility complex (MHC) class I interactions by ATP. Wijeyesakere SJ, Gagnon JK, Arora K, Brooks CL 3rd, Raghavan M.Proc Natl Acad Sci U S A. 2015 Oct 13;112(41):E5608-17. doi: 10.1073/pnas.1510132112. Epub 2015 Sep 29.

Author contact : Nancy Walls Research Professor of Microbiology and Immunology
University of Michigan Medical School
Ann Arbor, Michigan , USA

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