CALR

Overview

CALR (calreticulin) encodes an endoplasmic reticulum chaperone protein. Somatic frameshift insertions/deletions in exon 9 are recurrent driver mutations in myeloproliferative neoplasms (MPN), particularly essential thrombocythemia (ET) and primary myelofibrosis (MF). CALR mutations were the first somatic alterations reported in an ER chaperone in any cancer. Mutant CALR proteins lose the KDEL ER-retention signal and acquire a novel basic C-terminus, producing a proposed gain-of-function oncogene distinct from the JAK2/MPL signaling axis.

Alterations observed in the corpus

  • Recurrent exon 9 +1 bp frameshift indels (19 distinct variants; L367fs46 deletion and K385fs47 insertion dominant) in 70–84% of JAK2/MPL-negative MPN; mutually exclusive with JAK2 and MPL; first report of somatic mutations in an ER chaperone in any cancer; produces mutant protein with novel basic C-terminus lacking KDEL ER-retention signal PMID:24325359
  • Components of the MHC class I antigen-processing machinery (APM), including CALR, were enriched for somatic mutations in TIL-rich colorectal tumors, consistent with immune-escape selection PMID:27149842.

Cancer types (linked)

  • Myeloproliferative neoplasms (ET, MF): dominant driver in JAK2/MPL-negative cases; CALR-mutated ET presents with higher platelet counts, lower hemoglobin, and higher transformation-to-MF risk than JAK2-mutated ET PMID:24325359

Co-occurrence and mutual exclusivity

  • Strictly mutually exclusive with JAK2 V617F and MPL mutations in MPN PMID:24325359
  • Mutations arise in the HSC compartment at earliest phylogenetic node PMID:24325359

Therapeutic relevance

  • Loss of KDEL ER-retention signal and novel basic C-terminus suggest a gain-of-function mechanism distinct from JAK2/MPL, raising prospect of CALR-mutant-specific therapeutic strategies (not pursued experimentally in source paper) PMID:24325359

Open questions

  • CALR-mutated ET has higher MF-transformation risk than JAK2-mutated ET (P=0.03) but no survival difference was demonstrated in the discovery cohort; independent replication needed PMID:24325359
  • CALR indels are essentially MPN/MDS-restricted (none in 287 lymphoid cancers, 502 solid tumors, or 1015 cell lines), but the oncogenic mechanism of the novel C-terminus is not yet resolved PMID:24325359

Sources

This page was processed by crosslinker on 2026-05-09. - PMID:27149842

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