Calreticulin (CALR) is a calcium-binding protein
that functions in calcium storage and transcription
regulation. Missense mutations, silent mutations, nonsense mutations, and frameshift insertions and deletions are
observed in cancers such as colorectal cancer, leukemias, myeloproliferative neoplasms, and
Last Updated: March 30, 2018
CALR in Myeloproliferative Neoplasms
CALR is the second-most frequently mutated gene
in MPNs following JAK2. Although patients diagnosed with ET and PMF carry CALR mutations at a rate of 20–25% (Klampfl et al.
et al. 2013), they are seldom observed in patients with PV (COSMIC; Chauveau et al. 2017).
CALR mutations in MPNs are usually exon 9 frameshift insertions and deletions.
Around 85% of CALR alterations are a 52-bp deletion (p.L367fs*46), also known as a type 1
mutation, or a 5-bp TTGTC insertion (p.K385fs*47), known as a type 2 mutation (Klampfl et al.
2013). In ET, CALR mutations are associated with younger age, male sex,
lower leukocyte and hemoglobin levels, improved survival, and fewer thrombotic events (Rotunno et al.
2013). In PMF, CALR mutations correlate with younger age, lower hemoglobin
levels, higher platelet counts, lower risk of thrombotic events, and longer survival when
compared to the JAK2-mutated patients (Klampfl et al.
CALR mutations lead to
ligand-independent activation of the JAK/STAT and MAP kinase
pathways by triggering the thrombopoietin receptor
(encoded by the MPL gene) (Araki et al.
et al. 2016; Marty
et al. 2016) and thus act as a driver mutation in MPNs. Preclinical studies have
shown that JAK inhibitors such as ruxolitinib and fedratinib blocked JAK-STAT signaling
resulting from mutated CALR in mice and zebrafish (Lim et al.
et al. 2016). A phase III clinical trial, COMFORT-II, showed the efficacy of
ruxolitinib in patients with CALR-mutated PMF (Guglielmelli et al. 2014).
Last Updated: April 3, 2018
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