• What is CALR?
  • CALR in Acute Myeloid Leukemia
  • CALR c.1154_1155insTTGTC (K385fs*47)
  • Clinical Trials

CALR

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 stomach cancer.

Last Updated: March 30, 2018

CALR in Acute Myeloid Leukemia

In a recent study, the frequency of CALR mutations in acute myeloid leukemia was found to be 1% (1 of 104 samples; Qiao et al. 2016). However, two separate studies using 135 and 254 patients, respectively, reported no CALR mutations in AML patients (Wang et al. 2016; Klampfl et al. 2013). To date, most CALR mutations in AML are exon 9 frameshift insertions and deletions—either a 52-bp deletion (p.L367fs*46), 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). Due in part to the rarity of CALR mutations in AML, it is unclear whether or how CALR mutations fit into the "two-hit" theory of leukemogenesis.

Last Updated: March 30, 2018

CALR c.1154_1155insTTGTC (K385fs*47) Mutation in Acute Myeloid Leukemia

Properties
Location of mutation Exon 9 (C-terminal domain)
Frequency of CALR mutations in AML 1% (Heuser et al. 2014; Qiao et al. 2016)
Frequency of CALR K385fs*47 mutation in CALR-mutated AML 0.5% (Heuser et al. 2014)
Implications for Targeted Therapeutics
Response to JAK inhibitors Unknown at this timea

The CALR K385fs*47 mutation, also referred to as type 2 mutation, is the second-most frequently occurring somatic mutation in the CALR gene (COSMIC) following CALR L367fs*46. This mutation causes a 5-bp deletion and a frameshift in exon 9, leading to a loss of all the negatively charged amino acids from the C-terminus of the CALR protein (Klampfl et al. 2013). Mice with a type 1 mutation developed rapid thrombocytosis and a myelofibrosis phenotype and displayed a higher tendency towards disease progression as compared to mice with a type 2 mutation (Marty et al. 2014). The prognostic significance of this mutation is unclear.

a Preclinical studies have shown that JAK inhibitors such as ruxolitinib and fedratinib block JAK-STAT signaling resulting from mutated CALR in mice and zebrafish (Lim et al. 2016; Shide et al. 2016). A phase III clinical trial, COMFORT-II, showed the efficacy of ruxolitinib in patients with CALR-mutated primary myelofibrosis (Guglielmelli et al. 2014).​

Last Updated: March 30, 2018

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