JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes

Rumi, Elisa; Pietra, Daniela; Ferretti, Virginia Valeria; Klampfl, Thorsten; Harutyunyan, Ashot S.; Milosevic, Jelena D.; Them, Nicole C.C.; Berg, Tiina; Elena, Chiara; Casetti, Ilaria Carola; Milanesi, Chiara; Sant’Antonio, Emanuela; Bellini, Marta; Fugazza, Elena; Renna, Maria C.; Boveri, Emanuela; Astori, Cesare; Pascutto, Cristiana; Královics, Róbert; Cazzola, Mario

doi:10.1182/blood-2013-11-539098

Cited by 525 publications

(620 citation statements)

References 37 publications

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“…Nangalia et al reported that CALR mutated ET patients presented with significantly higher platelet counts and lower hemoglobin than JAK2 mutated counterparts [2]. Findings in ET patients have subsequently been validated in two independent series [9,10]. In one study that included 576 patients with 2008 WHO-defined ET, 64.1% of whom were JAK2V617F mutated, 4.3% MPLW515 mutated, 15.5% CALR mutated (corresponding to 48.9% of JAK2 and MPL unmutated) and 16.1% triple negative (JAK2, MPL and CALR unmutated) patients [10], CALR mutated patients were predominantly male with lower leukocyte and hemoglobin levels and higher platelet counts than JAK2V617F mutated counterparts.…”

Section: Calreticulin Mutations In Mpn: Relevance For Diagnosis and Pmentioning

confidence: 92%

“…Of importance, these subjects had longer thrombosis-free survival, and a thrombotic rate that was about onethird lower than JAK2V617F and MPLW515 mutated and similar to triple negative patients. Preliminary evidence, although not in a multivariate analysis, also indicated that CALR mutated ET patients had a lower incidence of transformation to either PV or acute leukemia compared with JAK2V617F mutated [9], whereas the incidence of PET-MF was similar to JAK2 and MPL mutated patients [9,10]. In summary, current evidence suggests that ET patients with CALR mutations are at lower risk of thrombosis and hematologic progression than those harboring the JAK2V617F mutations and this may have implications for risk stratification and management.…”

Section: Calreticulin Mutations In Mpn: Relevance For Diagnosis and Pmentioning

confidence: 94%

“…Moreover, provided such assays allow for more accurate estimation of allele burden than current methods, it is still unclear whether such quantification has diagnostic, phenotypic or prognostic relevance. Nevertheless, it has been reported that the median allele burden for the two commonest CALR mutations was 32% in ET patients at diagnosis compared with 50% in those with PET-MF suggesting that disease progression may be associated with accumulation of mutated CALR alleles [9].…”

Section: Calreticulin Mutations In Mpn: Relevance For Diagnosis and Pmentioning

confidence: 99%

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CALR mutations in myeloproliferative neoplasms: Hidden behind the reticulum

et al. 2014

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Four seminal studies published in 2005 showed that the classic Philadelphia-chromosome negative chronic myeloproliferative neoplasms (MPNs) are characterized by a recurrent V617F point mutation in exon 14 of JAK2 [1]. This somatic mutation is found in the vast majority of patients with polycythemia vera (PV) and 60% of those with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Virtually all patients with post-polycythemia vera (PPV-) and greater than 60% of patients with post-essential thrombocythemia (PET-) myelofibrosis are JAK2V617F mutated. Mitotic recombination of chromosome 9p is frequent in MPNs and leads to the copy-neutral loss of heterozygosity (CN-LOH) for JAK2 that results in homozygosity for the mutated allele. In the minority of PV patients that do not carry JAK2V617F, other JAK2 mutations have been found in roughly half of cases, such as insertions or deletions in exon 12, and overall 99% of PV patients carry a mutation in JAK2. Amongst the 40% of patients with ET and MF that are JAK2V617F negative 3-5% carry mutations at codon 515 of the gene encoding the thrombopoietin receptor (MPL) and CN-LOH of chromosome 1p underlies the transition from heterozygous to homozygous MPLW515 mutations. Both JAK2 and MPL mutations are gain-of-function and promote the over-activation of STAT signaling largely mediated by abnormal and sustained phosphorylation of JAK2. Targeting activated JAK2 with JAK inhibitors is changing the therapeutic landscape of myelofibrosis, and the JAK2 and JAK1 inhibitor ruxolitinib has been approved as the first-in-class drug for the treatment of myelofibrosis; in addition, a number of phase II-III trials with different JAK2 inhibitors are ongoing in PV.The close association of JAK2V617F mutation with MPNs led to a revision of the WHO diagnostic criteria in 2008, where JAK2V617F and others closely related mutations, such as JAK2 exon 12 and MPLW515 mutations, were elected to represent new major diagnostic criteria for the three classic MPNs . Subsequent studies highlighted an unexpected complexity of the mutational landscape of MPNs with co-mutation of several other genes identified in up to 25-30% of the patients [1]. However, these mutations are not specific to MPNs as they are present in patients with other myeloid disorders such as chronic myelomonocytic leukemia, myelodysplastic syndrome (MDS), and acute leukemia. The spectrum of genes mutated involves epigenetic regulation (EZH2, ASXL1, TET2, DNMT3A, IDH1, and IDH2), the spliceosome (SF3B1, SRSF2, U2AF1) and rarer targets that disrupt JAK-STAT signalling (SH2B3/LNK). As a result of their distribution across myeloid malignancies they do not represent suitable diagnostic markers for classic MPNs but may find application for prognostic assessment, at least in PMF. However, the molecular complexity of MPNs is still far from being fully appreciated and other nonrecurrent mutations are expected to be discovered by application of deep sequencing approaches. Calreticulin Mutations in MPN: Filling the GapThe "black box" tha...

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Section: Calreticulin Mutations In Mpn: Relevance For Diagnosis and Pmentioning

confidence: 92%

Section: Calreticulin Mutations In Mpn: Relevance For Diagnosis and Pmentioning

confidence: 94%

Section: Calreticulin Mutations In Mpn: Relevance For Diagnosis and Pmentioning

confidence: 99%

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CALR mutations in myeloproliferative neoplasms: Hidden behind the reticulum

et al. 2014

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“…7,8 In ET, CALR mutations correlated with male sex, younger age, lower leukocyte count, lower hemoglobin level and higher platelet count 8 and in PMF with younger age, higher platelet count and lower incidences of anemia, leukocytosis and spliceosome mutations. 7 Furthermore, CALR mutations in ET were associated with longer thrombosis-free survival 8,9 and in PMF with longer overall survival. 7 Before the discovery of CALR mutations in ET and PMF, we had identified mutant ASXL1 as dynamic international prognostic scoring system (DIPSS)-plus 10 and IPSS 11 independent risk factor for survival in PMF.…”

Section: Introductionmentioning

confidence: 99%

CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients

et al. 2014

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“…Laboratory tests showed a WBC of 30 600/µL and a platelet count of 1 031 000/µL, in association with high serum soluble IL2‐receptor (1001 U/mL), low serum IgG (712 mg/dL), and low complement CH50 levels (5 U/mL). Essential thrombocythemia (ET)1 was suspected, but JAK2 V617F gene mutation was negative. An abdominal CT revealed a huge mass within the spleen (Figure 1A).…”

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confidence: 99%