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.
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
authors.forename: Emnet A
authors.initials: EA
authors.lastname: Wassie
authors.forename: Paola
authors.initials: P
authors.lastname: Guglielmelli
authors.forename: Naseema
authors.initials: N
authors.lastname: Gangat
authors.forename: Alem A
authors.initials: AA
authors.lastname: Belachew
authors.forename: Terra L
authors.initials: TL
authors.lastname: Lasho
authors.forename: Christy
authors.initials: C
authors.lastname: Finke
authors.forename: Rhett P
authors.initials: RP
authors.lastname: Ketterling
authors.forename: Curtis A
authors.initials: CA
authors.lastname: Hanson
authors.forename: Animesh
authors.initials: A
authors.lastname: Pardanani
authors.forename: Alexandra P
authors.initials: AP
authors.lastname: Wolanskyj
authors.forename: Margherita
authors.initials: M
authors.lastname: Maffioli
authors.forename: Rosario
authors.initials: R
authors.lastname: Casalone
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pacilli
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
authors.forename: Francesco
authors.initials: F
authors.lastname: Passamonti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D064032:Calbindin 2 / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D015870:Gene Expression; D006454:Hemoglobins; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D007958:Leukocyte Count; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D016019:Survival Analysis; D013920:Thrombocythemia, Essential / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D034061:Thrombopoiesis / Q000235:genetics*
chemical_list: C576764:CALB2 protein, human; D064032:Calbindin 2; D006454:Hemoglobins; C507924:JAK2 protein, human; D053614:Janus Kinase 2