Work

Immune surveillance and emerging immunogenetic modifiers in CALR-mutated myeloproliferative neoplasms

Year: 2026

Type: article

Abstract: Calreticulin ( CALR ) exon 9 mutations define a major molecular subgroup of essential thrombocythemia and primary myelofibrosis. Although the oncogenic interaction between mutant CALR and the thrombopoietin receptor MPL is well established, the factors that influence whether a newly arising CALR-mutant hematopoietic clone is eliminated, contained, or allowed to expand remain incompletely understood. The shared neomorphic C-terminal sequence generated by pathogenic CALR mutations creates an unusual model for studying driver-specific cancer immunoediting. Evidence accumulated over the past decade indicates that mutant CALR can elicit CD4+ and CD8+ T-cell responses, yet naturally occurring and vaccine-induced immunity is frequently insufficient to control disease. Host immunogenetic variation may contribute to this discrepancy. HLA class I and class II genotypes influence the repertoire of mutant CALR-derived peptides that can be stably presented to T cells, whereas antigen processing additionally depends on proteasomal or endosomal cleavage, TAP transport, peptide-loading machinery, source-protein abundance, and other cellular factors. In parallel, natural killer cell surveillance is influenced by the NKG2D-MICA/MICB axis and by inhibitory KIR-HLA interactions. Recent studies have linked HLA genotypes, MICA / MICB and KLRK1 variation, and KIR receptor-ligand combinations to susceptibility to CALR -mutated or related myeloproliferative neoplasms, although most observations remain exploratory and have not been independently replicated. This review integrates direct CALR-mutated MPN evidence with comparative evidence from other MPN subtypes and mechanistic evidence from other malignancies or experimental systems, while explicitly distinguishing their levels of support. Current data support a model in which oncogenic signaling, inherited immune-recognition capacity, and acquired immune escape may jointly contribute to the evolutionary trajectory of CALR-mutant clones. Multicenter, ancestry-matched and functionally integrated studies are required before immunogenetic markers can be translated into clinical practice.

Source: Frontiers in Hematology

DOI: 10.3389/frhem.2026.1969104

Authors: Velizar Shivarov, Milena Ivanova

Institutions: Medical University Pleven, Alexandrovska Hospital, Medical University of Sofia

Language: English

Topic: Myeloproliferative Neoplasms: Diagnosis and Treatment

Subfield: Genetics (clinical)

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,353