CALR mutation studies in chronic neutrophilic leukemia
Correspondence: Somatic mutations in calreticulin (CALR), a gene which has not previously been shown to be oncogenic, have recently been identified in BCR-ABL1-negative myeloproliferative neoplasms (MPN).[1, 2] These mutations were mutually exclusive of JAK2 and MPL mutations and their frequencies in strictly World Health Organization (WHO)-defined disease were 49% and 74% in JAK2/MPL-unmutated ET and PMF, respectively.[3, 4] CALR mutations have infrequently been reported in other myeloid malignancies including refractory anemia with ring sideroblasts and marked thrombocytosis (13% of 24 patients), myelodysplastic syndromes (8.3% of 120 patients), chronic myelomonocytic leukemia (3% of 33 patients) and atypical chronic myelomonocytic leukemia (3.4% of 29 patients).[1, 2] Considering the fact that chronic neutrophilic leukemia (CNL) is morphologically akin to other MPN, it is important to examine its potential association with CALR mutations. We performed CALR mutation analysis in 26 cases of clinically suspected CNL, including 8 patients whose diagnosis was confirmed by strict WHO criteria.[5] All (100%) of the 8 WHO-defined CNL cases carried a CSF3R mutation, including 6 patients with CSF3RT618I.[5] Three of the latter 6 patients also expressed SETBP1 mutations. Bone marrow-derived DNA was used for CALR mutation screening using previously published methods.[4].Our results revealed a novel CALR nucleotide variant (CALRE398D c.1194G>T) in one case of CNL who was also harboring CSF3RT618I and SETBP1G870D (Figure 1), resulting in the amino acid substitution of glutamic acid with aspartic acid at amino acid position 398. All CALR mutations currently described in MPN affect exon 9 and were somatic insertions or deletions that resulted in a 1+ base pair frame shift, and generation of an altered C-terminal. CALR exon 9 point mutations have rarely been reported in lymphoma (CALRE405Q and CALRE403X)[6] and PMF
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/ajh.23665
American Journal of Hematology
(CALRE379D).[1] The consequences of an amino acid substitution is not yet known, but the identification of mutations that do not result in generation of a unique C-terminus is suggestive of a different pathogenetic mechanism.
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Acknowledgments: None.
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American Journal of Hematology
Conflict of interest: All authors disclose no conflict of interest.
John Wiley & Sons
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References
1.
Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in
myeloproliferative neoplasms. The New England journal of medicine 2013;369:2379-2390.
2.
Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative
neoplasms with nonmutated JAK2. The New England journal of medicine 2013;369:2391-2405.
3.
Rotunno G, Mannarelli C, Guglielmelli P, et al. Impact of Calreticulin Mutations on Clinical and
Hematological Phenotype and Outcome in Essential Thrombocythemia. Blood 2013.
4.
Tefferi A, Lasho T, Finke C, et al. CALR vs JAK2 vs MPL mutated or triple-negative
myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia 2014.
5.
Pardanani A, Lasho TL, Laborde RR, et al. CSF3R T618I is a highly prevalent and specific
mutation in chronic neutrophilic leukemia. Leukemia 2013;27:1870-1873.
6.
Green MR, Gentles AJ, Nair RV, et al. Hierarchy in somatic mutations arising during genomic
evolution and progression of follicular lymphoma. Blood 2013;121:1604-1611.
John Wiley & Sons
American Journal of Hematology
Terra L. Lasho1, Michelle A. Elliott MD1, Animesh Pardanani MBBS PhD1, and Ayalew Tefferi MD1
1
Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN;
*Corresponding author: Prof. Ayalew Tefferi, MD, Division of Hematology, Department of Medicine, Mayo Clinic, Rochester MN 55905, USA, Tel: +1 507 284 3159, Fax: +1 507 266 4972, [email protected]
Text word count: 312 Figures: 1 Tables: 0
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American Journal of Hematology
Figure 1. CALR missense mutation in a WHO-defined case of CNL. This results in a G>T change at nucleotide position 1194, and amino acid change: CALRE398D. 254x190mm (96 x 96 DPI)
John Wiley & Sons
Correspondence: Somatic mutations in calreticulin (CALR), a gene which has not previously been shown to be oncogenic, have recently been identified in BCR-ABL1-negative myeloproliferative neoplasms (MPN).[1, 2] These mutations were mutually exclusive of JAK2 and MPL mutations and their frequencies in strictly World Health Organization (WHO)-defined disease were 49% and 74% in JAK2/MPL-unmutated ET and PMF, respectively.[3, 4] CALR mutations have infrequently been reported in other myeloid malignancies including refractory anemia with ring sideroblasts and marked thrombocytosis (13% of 24 patients), myelodysplastic syndromes (8.3% of 120 patients), chronic myelomonocytic leukemia (3% of 33 patients) and atypical chronic myelomonocytic leukemia (3.4% of 29 patients).[1, 2] Considering the fact that chronic neutrophilic leukemia (CNL) is morphologically akin to other MPN, it is important to examine its potential association with CALR mutations. We performed CALR mutation analysis in 26 cases of clinically suspected CNL, including 8 patients whose diagnosis was confirmed by strict WHO criteria.[5] All (100%) of the 8 WHO-defined CNL cases carried a CSF3R mutation, including 6 patients with CSF3RT618I.[5] Three of the latter 6 patients also expressed SETBP1 mutations. Bone marrow-derived DNA was used for CALR mutation screening using previously published methods.[4].Our results revealed a novel CALR nucleotide variant (CALRE398D c.1194G>T) in one case of CNL who was also harboring CSF3RT618I and SETBP1G870D (Figure 1), resulting in the amino acid substitution of glutamic acid with aspartic acid at amino acid position 398. All CALR mutations currently described in MPN affect exon 9 and were somatic insertions or deletions that resulted in a 1+ base pair frame shift, and generation of an altered C-terminal. CALR exon 9 point mutations have rarely been reported in lymphoma (CALRE405Q and CALRE403X)[6] and PMF
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/ajh.23665
American Journal of Hematology
(CALRE379D).[1] The consequences of an amino acid substitution is not yet known, but the identification of mutations that do not result in generation of a unique C-terminus is suggestive of a different pathogenetic mechanism.
John Wiley & Sons
Page 2 of 7
Page 3 of 7
American Journal of Hematology
Acknowledgments: None.
John Wiley & Sons
American Journal of Hematology
Conflict of interest: All authors disclose no conflict of interest.
John Wiley & Sons
Page 4 of 7
Page 5 of 7
American Journal of Hematology
References
1.
Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in
myeloproliferative neoplasms. The New England journal of medicine 2013;369:2379-2390.
2.
Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative
neoplasms with nonmutated JAK2. The New England journal of medicine 2013;369:2391-2405.
3.
Rotunno G, Mannarelli C, Guglielmelli P, et al. Impact of Calreticulin Mutations on Clinical and
Hematological Phenotype and Outcome in Essential Thrombocythemia. Blood 2013.
4.
Tefferi A, Lasho T, Finke C, et al. CALR vs JAK2 vs MPL mutated or triple-negative
myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia 2014.
5.
Pardanani A, Lasho TL, Laborde RR, et al. CSF3R T618I is a highly prevalent and specific
mutation in chronic neutrophilic leukemia. Leukemia 2013;27:1870-1873.
6.
Green MR, Gentles AJ, Nair RV, et al. Hierarchy in somatic mutations arising during genomic
evolution and progression of follicular lymphoma. Blood 2013;121:1604-1611.
John Wiley & Sons
American Journal of Hematology
Terra L. Lasho1, Michelle A. Elliott MD1, Animesh Pardanani MBBS PhD1, and Ayalew Tefferi MD1
1
Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN;
*Corresponding author: Prof. Ayalew Tefferi, MD, Division of Hematology, Department of Medicine, Mayo Clinic, Rochester MN 55905, USA, Tel: +1 507 284 3159, Fax: +1 507 266 4972, [email protected]
Text word count: 312 Figures: 1 Tables: 0
John Wiley & Sons
Page 6 of 7
Page 7 of 7
American Journal of Hematology
Figure 1. CALR missense mutation in a WHO-defined case of CNL. This results in a G>T change at nucleotide position 1194, and amino acid change: CALRE398D. 254x190mm (96 x 96 DPI)
John Wiley & Sons
