CALR mutations in myeloproliferative neoplasms: An unfolding story (2024)

  • Journal List
  • EXCLI J
  • v.19; 2020
  • PMC7726487

As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsem*nt of, or agreement with, the contents by NLM or the National Institutes of Health.
Learn more: PMC Disclaimer | PMC Copyright Notice

CALR mutations in myeloproliferative neoplasms: An unfolding story (1)

Link to Publisher's site

Stephen E. Langabeer*,1

Author information Article notes Copyright and License information PMC Disclaimer



Dear Editor,

The discovery of mutations in CALR, the gene that encodes calreticulin, in a significant proportion of patients with the myeloproliferative neoplasms (MPN) of essential thrombocythemia (ET) and primary myelofibrosis (PMF) drastically altered the molecular landscape of these diseases (Klampfl et al., 2013[4]; Nangalia et al., 2013[6]). The C-terminal of the calreticulin protein includes an endoplasmic reticulum (ER) KDEL retention signal that has a strong calcium-binding capacity thus acting as a calcium storage protein. Additionally, CALR acts as a molecular chaperone enabling glycoprotein folding in the ER. Nearly all mutations of CALR are either insertions, deletions or insertion and deletions (indels) that result in a loss of the terminal KDEL signal. Mutant CALR interacts with the thrombopoietin receptor MPL by a unique mechanism resulting in constitutive activation of the downstream JAK-STAT pathway and cellular transformation (Edahiro et al., 2020[2]).

Early studies suggested that CALR indel mutations were found inclusively in ET and PMF however expanded screening has uncovered sporadic cases exhibiting a polycythemic phenotype (Broséus et al., 2014[1]; Langabeer et al., 2017[5]). As CALR mutations are absent in polycythemia vera (PV; which is defined by the presence of JAK2 mutations), this most likely represents one end of the phenotypic spectrum of CALR-mutated MPN. More recently, mutations in the 3' untranslated region of CALR, an area not covered by conventional diagnostic approaches, have been identified in patients phenotypically resembling PV (Quattrocchi et al., 2020[7]).

A variety of molecular diagnostic platforms exist to detect CALR mutations such as capillary electrophoresis, real-time PCR, and increasingly, next-generation sequencing. Both deep sequencing and capillary electrophoresis screening have revealed a complexity of CALR mutations as evidenced by co-existing, multiple indels which would not be revealed by use of real-time screening for the most common CALR exon 9 indels (Jeromin et al., 2016[3]; Verger et al., 2020[9]).

A further confounding observation is the low frequency of in-frame CALR indels that would be predicted to retain the terminal KDEL region in some patients with features hematologically suggestive of an MPN (Szuber et al., 2016[8]; Verger et al., 2020[9]). These in-frame mutations have an allelic frequency of approximately 50 %, hence suggestive of a polymorphism, and although not diagnostic of an MPN, require further functional characterization.

Taken together, these more recent findings further underscore the clonal complexity of CALR-mutated MPN and provide a continuing challenge for improvement of molecular diagnostics algorithms.

Conflict of interest

The author declares no conflict of interest.

References

1. Broséus J, Park JH, Carillo S, Hermouet S, Girodon F. Presence of calreticulin mutations in JAK2-negative polycythemia vera. Blood. 2014;124:3964–3966. [PubMed] [Google Scholar]

2. Edahiro Y, Araki M, Komatsu N. Mechanism underlying the development of myeloproliferative neoplasms through mutant calreticulin. Cancer Sci. 2020;111:2682–2688. [PMC free article] [PubMed] [Google Scholar]

3. Jeromin S, Kohlmann A, Meggendorfer M, Schindela S, Perglerová K, Nadarajah N, et al. Next-generation deep-sequencing detects multiple clones of CALR mutations in patients with BCR-ABL1 negative MPN. Leukemia. 2016;30:973–976. [PubMed] [Google Scholar]

4. Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379–2390. [PubMed] [Google Scholar]

5. Langabeer SE, Haslam K, Flynn CM. Isolated erythrocytosis associated with a CALR mutation. Blood Cells Mol Dis. 2017;66:6–7. [PubMed] [Google Scholar]

6. Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369:2391–2405. [PMC free article] [PubMed] [Google Scholar]

7. Quattrocchi A, Maiorca C, Billi M, Tomassini S, De Marinis E, Cenfra N, et al. Genetic lesions disrupting calreticulin 3'-untranslated region in JAK2 mutation negative polycythemia vera. Am J Hematol. 2020;95:E263–E267. [PubMed] [Google Scholar]

8. Szuber N, Lamontagne B, Busque L. Novel germline mutations in the calreticulin gene: implications for the diagnosis of myeloproliferative neoplasms. J Clin Pathol. 2016;69:1033–1036. [PubMed] [Google Scholar]

9. Verger E, Maslah N, Schlageter MH, Chomienne C, Kiladjian JJ, Giraudier S, et al. Pitfalls in CALR exon 9 mutation detection: a single-center experience in 571 positive patients. Int J Lab Hematol. 2020:epub ahead of print. doi:10.111/ijlh.13282.. doi:10.1111/ijlh.13282. Available from: [PubMed] [CrossRef] [CrossRef] [Google Scholar]

Articles from EXCLI Journal are provided here courtesy of Leibniz Research Centre for Working Environment and Human Factors

CALR mutations in myeloproliferative neoplasms: An unfolding story (2024)

References

Top Articles
Latest Posts
Article information

Author: Mrs. Angelic Larkin

Last Updated:

Views: 6089

Rating: 4.7 / 5 (47 voted)

Reviews: 94% of readers found this page helpful

Author information

Name: Mrs. Angelic Larkin

Birthday: 1992-06-28

Address: Apt. 413 8275 Mueller Overpass, South Magnolia, IA 99527-6023

Phone: +6824704719725

Job: District Real-Estate Facilitator

Hobby: Letterboxing, Vacation, Poi, Homebrewing, Mountain biking, Slacklining, Cabaret

Introduction: My name is Mrs. Angelic Larkin, I am a cute, charming, funny, determined, inexpensive, joyous, cheerful person who loves writing and wants to share my knowledge and understanding with you.