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A rare CALR exon 9 mutation p.E379Vfs*53 in AYA generation exhibits gain-of-function nature and can induce essential thrombocythemia; a case report

Nagaharu, Keiki LU orcid ; Ono, Ryoichi ; Nakano, Eri ; Nakamura, Akihide ; Iwayama, Rukia ; Ikejiri, Makoto ; Oka, Koji ; Ohishi, Kohshi ; Nosaka, Tetsuya and Tawara, Isao , et al. (2025) In Hematology (United Kingdom) 30(1).
Abstract

Objectives: Current therapeutic strategies for essential thrombocythemia (ET) are mainly considered to prevent thrombo-hemorrhagic events, without increasing the rate of fibrotic progression or leukemic evolution. To treat the patients appropriately, the precise diagnosis of ET is essential. Although approximately 30% of ET cases are diagnosed as CALR mutation-positive; commercially available polymerase chain reaction-based methods for CALR mutation can detect only a limited variation of CALR mutations. We report the case of a 29-year-old woman admitted to our hospital because of thrombocytosis for 3 years. Leukocytosis, erythrocytosis, and JAK2 V617F and MPL mutations were not detected. Results: CALR mutation analysis for types 1–5 was... (More)

Objectives: Current therapeutic strategies for essential thrombocythemia (ET) are mainly considered to prevent thrombo-hemorrhagic events, without increasing the rate of fibrotic progression or leukemic evolution. To treat the patients appropriately, the precise diagnosis of ET is essential. Although approximately 30% of ET cases are diagnosed as CALR mutation-positive; commercially available polymerase chain reaction-based methods for CALR mutation can detect only a limited variation of CALR mutations. We report the case of a 29-year-old woman admitted to our hospital because of thrombocytosis for 3 years. Leukocytosis, erythrocytosis, and JAK2 V617F and MPL mutations were not detected. Results: CALR mutation analysis for types 1–5 was negative, however Sanger sequencing identified a novel mutation, c.1136–1142 del7 insTCCTCTGTCCTT. In vitro assay revealed this mutation as a gain-of-function mutation where the C-terminus of calreticulin is altered. In silico analysis showed that the current mutation is considered as type-I CALR mutation like category, which is considered more likely to develop overt myelofibrosis. Conclusion: Our findings emphasize the importance of thorough genetic screening for patients with thrombocytosis, including those who standard CALR mutation assays produce negative results. In view of prognostic risk classification, identifying such novel mutations and determining their functional consequences can substantially improve the diagnostic accuracy and may provide future therapeutic opportunity.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CALR mutation, calreticulin, Essential thrombocythemia
in
Hematology (United Kingdom)
volume
30
issue
1
article number
2513190
publisher
Informa Healthcare
external identifiers
  • scopus:105007660381
  • pmid:40474352
ISSN
1024-5332
DOI
10.1080/16078454.2025.2513190
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
id
323a63df-d068-47a4-94d2-a3d6bd4cb1e4
date added to LUP
2025-12-22 13:22:05
date last changed
2025-12-22 13:23:14
@article{323a63df-d068-47a4-94d2-a3d6bd4cb1e4,
  abstract     = {{<p>Objectives: Current therapeutic strategies for essential thrombocythemia (ET) are mainly considered to prevent thrombo-hemorrhagic events, without increasing the rate of fibrotic progression or leukemic evolution. To treat the patients appropriately, the precise diagnosis of ET is essential. Although approximately 30% of ET cases are diagnosed as CALR mutation-positive; commercially available polymerase chain reaction-based methods for CALR mutation can detect only a limited variation of CALR mutations. We report the case of a 29-year-old woman admitted to our hospital because of thrombocytosis for 3 years. Leukocytosis, erythrocytosis, and JAK2 V617F and MPL mutations were not detected. Results: CALR mutation analysis for types 1–5 was negative, however Sanger sequencing identified a novel mutation, c.1136–1142 del7 insTCCTCTGTCCTT. In vitro assay revealed this mutation as a gain-of-function mutation where the C-terminus of calreticulin is altered. In silico analysis showed that the current mutation is considered as type-I CALR mutation like category, which is considered more likely to develop overt myelofibrosis. Conclusion: Our findings emphasize the importance of thorough genetic screening for patients with thrombocytosis, including those who standard CALR mutation assays produce negative results. In view of prognostic risk classification, identifying such novel mutations and determining their functional consequences can substantially improve the diagnostic accuracy and may provide future therapeutic opportunity.</p>}},
  author       = {{Nagaharu, Keiki and Ono, Ryoichi and Nakano, Eri and Nakamura, Akihide and Iwayama, Rukia and Ikejiri, Makoto and Oka, Koji and Ohishi, Kohshi and Nosaka, Tetsuya and Tawara, Isao and Sugimoto, Yuka}},
  issn         = {{1024-5332}},
  keywords     = {{CALR mutation; calreticulin; Essential thrombocythemia}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Informa Healthcare}},
  series       = {{Hematology (United Kingdom)}},
  title        = {{A rare CALR exon 9 mutation p.E379Vfs*53 in AYA generation exhibits gain-of-function nature and can induce essential thrombocythemia; a case report}},
  url          = {{http://dx.doi.org/10.1080/16078454.2025.2513190}},
  doi          = {{10.1080/16078454.2025.2513190}},
  volume       = {{30}},
  year         = {{2025}},
}