Calreticulin mutations in essential thrombocythemia and primary myelofibrosis.
Key claim: CALR exon 9 mutations serve as critical diagnostic and prognostic biomarkers in JAK2/MPL-unmutated ET and PMF, but their clinical utility is maximized only through integrated clinicopathologic and molecular testing rather than standalone assay use.
Abstract
Mutations in calreticulin have been identified as driver mutations in BCR-ABL1-negative myeloproliferative neoplasms (MPNs) and are especially important for diagnostics and prognosis in primary myelofibrosis and essential thrombocythemia. The vast majority of pathogenic variants are insertions or deletions in exon 9 that result in a mutant C-terminal sequence that activates the signaling of the thrombopoietin receptor, which in turn promotes megakaryocytic proliferation. This review examines the potential clinical utility of calreticulin mutations as laboratory biomarkers in essential thrombocythemia (ET) and primary myelofibrosis (PMF). It emphasizes their role in confirming clonality in JAK2/MPL-unmutated cases, distinguishing a clonal myeloproliferative disease from reactive thrombocytosis, clarifying the molecular interpretation, and guiding molecular diagnostic workflows. Special focus is placed on practical laboratory challenges, such as choosing assays, detecting rare and non-canonical variants in exon 9, analytical sensitivity, molecular reporting, and the integration of bone marrow morphology, cytogenetics, co-mutations, and next-generation sequencing. Overall, clinical information gained from calreticulin testing is greatest when it is used in an integrated clinicopathologic and molecular testing context rather than as a standalone test. To make calreticulin mutations more effectively used for diagnosis or prognosis in routine hematology practice, we need standardization of testing, harmonization of reporting, and prospective validation of risk-models based on both the subtypes and the burden of the mutation.
Why this matters
Pending synthesis.