CALRETICULIN: New Clinical Diagnostic Assay for Myeloproliferative Neoplasms

The Knight Diagnostic Laboratories have launched new clinical diagnostic assay for detecting the calreticulin  (CALR) gene mutations that have recently been shown to be common in myeloproliferative neoplasms (essential thrombocythemia and primary myelofibrosis). Together with the analysis of the JAK2 gene for the common V617F mutation (and to a lesser degree MPL mutations), this new assay will now allow a specific molecular marker to be identified (and potentially monitored) in the overwhelming majority (>90%) of patients with a myeloproliferative neoplasm. 

The calcium-binding endoplasmic reticulin chaperone protein Calreticulin (CALR) has recently been shown to be somatically mutated in the majority of patients with a myeloproliferative neoplasm that lack a mutation in the JAK2 gene. In particular, two independent groups (1, 2) have each recently found a variety of insertion or deletion mutations in exon 9 of the calreticulin gene in:

• ~70% of patients with JAK-negative essential thrombocythemia (ET)
• ~60-80% of patients with JAK2-negative primary myelofibrosis
• A minority of patients with myelodysplasia (8%)
• Zero patients with de novo acute myeloid leukemia, chronic myeloid leukemia, lymphoid leukemia, or solid tumors 

The detection of a CALR gene mutation may aid in the specific diagnosis of a myeloproliferative neoplasm, and help distinguish this clonal disease from a benign reactive process. After the MPN diagnosis is made, the presence of a CALR gene mutation also predicts a more indolent disease course with a lower thrombotic risk and longer overall survival (relative to those with a JAK2 mutation) (1). Although specific targeted therapy for calreticulin-mutated MPN patients has not yet been described, the in vitro expression of this mutation conveys cytokine-independent growth, activated STAT5 signaling, and sensitivity to JAK2 inhibitors (1).  The presence of a clonal CALR gene mutation may also allow minimal residual disease to be molecularly monitored during the course of therapy. 

Related Links

• CALRETICULIN (CALR) Gene Mutations in Myeloproliferative Neoplasms
• Requisition

References

1. K Thorsten et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. New Engl J Med online first publication, Dec 10, 2013. DOI: 10.1056/NEJMoa1311347
2. J Nangalia et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. New Engl J Med online first publication, Dec 10, 2013. DOI: 10.1056/NEJMoa1312542.