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 5 402) and validation (n 5 625) 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 5 0.005) and younger age with type-2 (P 5 0.001) variants. Notably, platelet count was significantly higher in type-2 vs. type-1 CALR-mutated patients (P 5 0.03) and the particular observation was validated in the validation cohort that included 111 CALR-mutated ET patients (P 5 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.

Calreticulin variant stratified driver mutational status and prognosis in essential thrombocythemia

“…However, this observation was not supported by subsequent other studies while other reports suggested differential prognostic effects from distinct mutant CALR variants in PMF [6,8,12,13]. In ET, patients with type 2 CALR mutations displayed significantly higher platelet count, compared to their counterparts with type 1 CALR mutations [17]. In the latter study, overall and thrombosis-free survivals (TFS) were similar between the two groups of CALR-mutated patients.…”

Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk‐stratification and management

“…JAK2 exon 12 mutation positive patients usually present with predominantly erythroid myelopoiesis, subnormal serum erythropoietin level and younger age at diagnosis, but were prognostically similar to JAK2V617F [28]. In ET, mutant CALR (vs. JAK2) was associated with younger age, male sex, higher platelet count, lower hemoglobin level, lower leukocyte count, and lower incidence of thrombotic events [9][10][11][12]; Type 2 versus Type 1 CALR mutations were associated with higher platelet count [29]. In PMF, CALR-mutated patients were also younger and presented with higher platelet count, better risk profile, and lower frequencies of anemia, leukocytosis, and spliceosome mutations [13].…”

Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants

“…del52 and ins5 CALR mutants might stabilize 2 related, but not identical, active dimeric interfaces of TpoR, leading to differences in the phenotype, as suggested. 41,42 This hypothesis would also explain why CALR mutants are not seen in other cancers driven by N-glycosylated mutated receptors (eg, EGFR, EPOR, KIT, FLT3D). 6 Furthermore, binding of CALR mutant to TpoR and its activation do not require Tpo-binding.…”