With the recent discovery of somatic calreticulin (CALR) mutations in the majority of essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients lacking JAK2 or MPL mutations, Mayo Medical Laboratories now offers testing for the detection of CALR mutations.
CALR mutation analysis assists in diagnosis and prognosis of Philadelphia chromosome-negative myeloproliferative neoplasms.
- This assay provides rapid detection of insertion and deletion-type mutations in exon 9 of CALR
- CALR mutations:
Serve as an important diagnostic molecular marker in essential thrombocythemia (ET) and primary myelofibrosis (PMF)
- Assist in distinction between reactive thrombocytosis and/or leukocytosis versus a myeloproliferative neoplasm such as ET and PMF
- Are especially helpful to the pathologist in evaluation of bone marrows with ambiguous etiology of thrombocytosis, equivocal bone marrow morphologic findings of MPN, and/or unexplained reticulin fibrosis.
- Aid in prognostication of PMF and thrombosis risk assessment in ET.
- Are associated with better overall survival and JAK2, CALR, and MPL tripe-negative patients show inferior survival in PMF.1
Importance of CALR Testing in MPN Patients
The most frequent genetic mutation in the Philadelphia chromosome-negative myeloproliferative neoplasms (ET and PMF) is the JAK2V617F mutation, which is present in approximately 50% to 60% of these patients. The JAK2V617F serves as a confirmatory molecular marker of these diseases.
Mutations in the MPL gene are found in an additional 4% to 10% of ET and PMF cases. Somatic mutations (insertions and/or deletions) in exon 9 of the CALR gene were recently discovered to be the second most frequent somatic mutation (after JAK2V617F) in ET and PMF patients and appears to be mutually exclusive of the JAK2 and MPL mutations.2,.3 It has a reported frequency of approximately 50% to 90% in JAK2 and MPL-wild type (WT) ET and PMF, and importantly is not found in polycythemia vera (PV) patients.2-5
Therefore, a CALR mutation serves as an additional important diagnostic molecular marker in ET and PMF. CALR mutation status also has an important role in prognosis. For example, in PMF, a CALR mutation carries favorable survival impact and a triple-negative mutation status (JAK2, MPL and CALR-negative) has been identified as a high-risk molecular signature. CALR impact on survival in ET patient is uncertain, however, it is associated with lower risk of thrombosis in comparison to JAK2 and MPL mutations. 2,4,5
- Tefferi A , Lasho TL, Finke CM, et al: CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia advance online publication 21 January 2014; doi: 10.1038/leu.2014.3
- Klampfl T, Gisslinger H, Harutyunyan AS, et al: Somatic mutation of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013;369:2379-2390
- Nangalia J, Massie CE, Baxter EJ, et al: Somatic CALR mutation in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013;369:2391-2405
- Rumi E, Pietra D, Ferretti V, et al: JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood 2014;123 (10):1544-1551
- Rotunno G, Mannarelli C, Guglielmelli P, et al: Impact of Calreticulin Mutations on Clinical and Hematological Phenotype and Outcome in Essential Thrombocythemia. Blood 2014;123(10):1552-1555
- Lundberg P, Karow A, Nienhold R, et al: Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood 2014; 123(14):2220-2228