Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: A collaborative study of 1027 patients

Ayalew Tefferi, Emnet A. Wassie, Paola Guglielmelli, Naseema Gangat, Alem A. Belachew, Terra L. Lasho, Christy Finke, Rhett P. Ketterling, Curtis A. Hanson, Animesh D Pardanani, Alexandra P. Wolanskyj, Margherita Maffioli, Rosario Casalone, Annalisa Pacilli, Alessandro M. Vannucchi, Francesco Passamonti

Research output: Contribution to journalArticle

114 Citations (Scopus)

Abstract

CALR (calreticulin) trails JAK2 as the second most mutated gene in essential thrombocythemia (ET). Mutant CALR in ET is a result of frameshift mutations, caused by exon 9 deletions or insertions; type-1, 52-bp deletion (p.L367fs*46), and type-2, 5-bp TTGTC insertion (p.K385fs*47) variants constitute more than 80% of these mutations. The current study includes a total of 1027 patients divided into test (n=402) and validation (n=625) cohorts. Among the 402 ET patients in the test cohort, 227 (57%) harbored JAK2, 11 (3%) Myeloproliferative leukemia virus oncogene (MPL), and 114 (28%) CALR mutations; 12% were wild-type for all three mutations (i.e., triple-negative). Among the 114 patients with CALR mutations, 51 (45%) displayed type-1 and 44 (39%) type-2 variants; compared to mutant JAK2, both variants were associated with higher platelet and lower hemoglobin and leukocyte counts. However, male sex was associated with only type-1 (P=0.005) and younger age with type-2 (P=0.001) variants. Notably, platelet count was significantly higher in type-2 vs. type-1 CALR-mutated patients (P=0.03) and the particular observation was validated in the validation cohort that included 111 CALR-mutated ET patients (P=0.002). These findings, coupled with the recent demonstration of preferential expression of mutant and wild-type CALR in megakaryocytes, suggest differential effects of CALR variants on thrombopoiesis. Am. J. Hematol. 89:E121-E124, 2014.

Original languageEnglish (US)
JournalAmerican Journal of Hematology
Volume89
Issue number8
DOIs
StatePublished - 2014

Fingerprint

Calreticulin
Essential Thrombocythemia
Mutation
Thrombopoiesis
Frameshift Mutation
Megakaryocytes
Platelet Count
Leukocyte Count
Oncogenes
Exons
Leukemia
Hemoglobins
Blood Platelets
Observation
Viruses

ASJC Scopus subject areas

  • Hematology

Cite this

Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia : A collaborative study of 1027 patients. / Tefferi, Ayalew; Wassie, Emnet A.; Guglielmelli, Paola; Gangat, Naseema; Belachew, Alem A.; Lasho, Terra L.; Finke, Christy; Ketterling, Rhett P.; Hanson, Curtis A.; Pardanani, Animesh D; Wolanskyj, Alexandra P.; Maffioli, Margherita; Casalone, Rosario; Pacilli, Annalisa; Vannucchi, Alessandro M.; Passamonti, Francesco.

In: American Journal of Hematology, Vol. 89, No. 8, 2014.

Research output: Contribution to journalArticle

Tefferi, A, Wassie, EA, Guglielmelli, P, Gangat, N, Belachew, AA, Lasho, TL, Finke, C, Ketterling, RP, Hanson, CA, Pardanani, AD, Wolanskyj, AP, Maffioli, M, Casalone, R, Pacilli, A, Vannucchi, AM & Passamonti, F 2014, 'Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: A collaborative study of 1027 patients', American Journal of Hematology, vol. 89, no. 8. https://doi.org/10.1002/ajh.23743
Tefferi, Ayalew ; Wassie, Emnet A. ; Guglielmelli, Paola ; Gangat, Naseema ; Belachew, Alem A. ; Lasho, Terra L. ; Finke, Christy ; Ketterling, Rhett P. ; Hanson, Curtis A. ; Pardanani, Animesh D ; Wolanskyj, Alexandra P. ; Maffioli, Margherita ; Casalone, Rosario ; Pacilli, Annalisa ; Vannucchi, Alessandro M. ; Passamonti, Francesco. / Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia : A collaborative study of 1027 patients. In: American Journal of Hematology. 2014 ; Vol. 89, No. 8.
@article{552802ea0e624a20960dbe9311dca98a,
title = "Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: A collaborative study of 1027 patients",
abstract = "CALR (calreticulin) trails JAK2 as the second most mutated gene in essential thrombocythemia (ET). Mutant CALR in ET is a result of frameshift mutations, caused by exon 9 deletions or insertions; type-1, 52-bp deletion (p.L367fs*46), and type-2, 5-bp TTGTC insertion (p.K385fs*47) variants constitute more than 80{\%} of these mutations. The current study includes a total of 1027 patients divided into test (n=402) and validation (n=625) cohorts. Among the 402 ET patients in the test cohort, 227 (57{\%}) harbored JAK2, 11 (3{\%}) Myeloproliferative leukemia virus oncogene (MPL), and 114 (28{\%}) CALR mutations; 12{\%} were wild-type for all three mutations (i.e., triple-negative). Among the 114 patients with CALR mutations, 51 (45{\%}) displayed type-1 and 44 (39{\%}) type-2 variants; compared to mutant JAK2, both variants were associated with higher platelet and lower hemoglobin and leukocyte counts. However, male sex was associated with only type-1 (P=0.005) and younger age with type-2 (P=0.001) variants. Notably, platelet count was significantly higher in type-2 vs. type-1 CALR-mutated patients (P=0.03) and the particular observation was validated in the validation cohort that included 111 CALR-mutated ET patients (P=0.002). These findings, coupled with the recent demonstration of preferential expression of mutant and wild-type CALR in megakaryocytes, suggest differential effects of CALR variants on thrombopoiesis. Am. J. Hematol. 89:E121-E124, 2014.",
author = "Ayalew Tefferi and Wassie, {Emnet A.} and Paola Guglielmelli and Naseema Gangat and Belachew, {Alem A.} and Lasho, {Terra L.} and Christy Finke and Ketterling, {Rhett P.} and Hanson, {Curtis A.} and Pardanani, {Animesh D} and Wolanskyj, {Alexandra P.} and Margherita Maffioli and Rosario Casalone and Annalisa Pacilli and Vannucchi, {Alessandro M.} and Francesco Passamonti",
year = "2014",
doi = "10.1002/ajh.23743",
language = "English (US)",
volume = "89",
journal = "American Journal of Hematology",
issn = "0361-8609",
publisher = "Wiley-Liss Inc.",
number = "8",

}

TY - JOUR

T1 - Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia

T2 - A collaborative study of 1027 patients

AU - Tefferi, Ayalew

AU - Wassie, Emnet A.

AU - Guglielmelli, Paola

AU - Gangat, Naseema

AU - Belachew, Alem A.

AU - Lasho, Terra L.

AU - Finke, Christy

AU - Ketterling, Rhett P.

AU - Hanson, Curtis A.

AU - Pardanani, Animesh D

AU - Wolanskyj, Alexandra P.

AU - Maffioli, Margherita

AU - Casalone, Rosario

AU - Pacilli, Annalisa

AU - Vannucchi, Alessandro M.

AU - Passamonti, Francesco

PY - 2014

Y1 - 2014

N2 - CALR (calreticulin) trails JAK2 as the second most mutated gene in essential thrombocythemia (ET). Mutant CALR in ET is a result of frameshift mutations, caused by exon 9 deletions or insertions; type-1, 52-bp deletion (p.L367fs*46), and type-2, 5-bp TTGTC insertion (p.K385fs*47) variants constitute more than 80% of these mutations. The current study includes a total of 1027 patients divided into test (n=402) and validation (n=625) cohorts. Among the 402 ET patients in the test cohort, 227 (57%) harbored JAK2, 11 (3%) Myeloproliferative leukemia virus oncogene (MPL), and 114 (28%) CALR mutations; 12% were wild-type for all three mutations (i.e., triple-negative). Among the 114 patients with CALR mutations, 51 (45%) displayed type-1 and 44 (39%) type-2 variants; compared to mutant JAK2, both variants were associated with higher platelet and lower hemoglobin and leukocyte counts. However, male sex was associated with only type-1 (P=0.005) and younger age with type-2 (P=0.001) variants. Notably, platelet count was significantly higher in type-2 vs. type-1 CALR-mutated patients (P=0.03) and the particular observation was validated in the validation cohort that included 111 CALR-mutated ET patients (P=0.002). These findings, coupled with the recent demonstration of preferential expression of mutant and wild-type CALR in megakaryocytes, suggest differential effects of CALR variants on thrombopoiesis. Am. J. Hematol. 89:E121-E124, 2014.

AB - CALR (calreticulin) trails JAK2 as the second most mutated gene in essential thrombocythemia (ET). Mutant CALR in ET is a result of frameshift mutations, caused by exon 9 deletions or insertions; type-1, 52-bp deletion (p.L367fs*46), and type-2, 5-bp TTGTC insertion (p.K385fs*47) variants constitute more than 80% of these mutations. The current study includes a total of 1027 patients divided into test (n=402) and validation (n=625) cohorts. Among the 402 ET patients in the test cohort, 227 (57%) harbored JAK2, 11 (3%) Myeloproliferative leukemia virus oncogene (MPL), and 114 (28%) CALR mutations; 12% were wild-type for all three mutations (i.e., triple-negative). Among the 114 patients with CALR mutations, 51 (45%) displayed type-1 and 44 (39%) type-2 variants; compared to mutant JAK2, both variants were associated with higher platelet and lower hemoglobin and leukocyte counts. However, male sex was associated with only type-1 (P=0.005) and younger age with type-2 (P=0.001) variants. Notably, platelet count was significantly higher in type-2 vs. type-1 CALR-mutated patients (P=0.03) and the particular observation was validated in the validation cohort that included 111 CALR-mutated ET patients (P=0.002). These findings, coupled with the recent demonstration of preferential expression of mutant and wild-type CALR in megakaryocytes, suggest differential effects of CALR variants on thrombopoiesis. Am. J. Hematol. 89:E121-E124, 2014.

UR - http://www.scopus.com/inward/record.url?scp=84904401956&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84904401956&partnerID=8YFLogxK

U2 - 10.1002/ajh.23743

DO - 10.1002/ajh.23743

M3 - Article

C2 - 24753125

AN - SCOPUS:84904401956

VL - 89

JO - American Journal of Hematology

JF - American Journal of Hematology

SN - 0361-8609

IS - 8

ER -