Calreticulin gene exon 9 frameshift mutations in patients with thrombocytosis

Chi, Jianxiang; Nicolaou, Katerina; Nicolaidou, Vicky; Koumas, Laura; Mitsidou, Andrie; Pierides, Chryso; Manoloukos, Menelaos; Barbouti, K; Melanthiou, Frederiki; Prokopiou, Chrystalla; Vassiliou, George S.; Costeas, Paul

doi:10.1038/leu.2013.382

Cited by 50 publications

(47 citation statements)

References 15 publications

(15 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our present data, showing distinct clinical characteristics of CALR mut ET subgroups in comparison with JAK2 mut cohorts, confirmed previous observations regarding younger age, sex distribution with less prominent female abundance (only in the ET subgroup), lower hemoglobin concentration, lower white blood cell counts (not significant in our PMF cohort), and higher platelet counts. [8][9][10][11][12] Considering venous thrombosis and other coagulation complications, our observations confirmed previous findings describing a lower risk of thrombosis in patients with CALR mut ET than in those with JAK2 mut ET. 8 In their extended cohort, Rumi et al 12 found that the rates of thrombosis at diagnosis in the CALR mut and JAK2 mut groups were 2.8% and 7.1%, respectively (P=0.059), and observed a reduced cumulative incidence of thrombosis (25 versus 10 events per 1000 person-years) in CALR mut patients (P=0.001).…”

Section: Discussionsupporting

confidence: 82%

“…8,9 Concurrent JAK2 and CALR mutations were reported in only two individuals in subsequent studies. 13,14 Confirming earlier observations in different MPN cohorts, [8][9][10]13 we found a similar frequency of CALR mutations in an independent group of MPN patients, with the frequency of these mutations being high (121/162, 75%) among JAK2 V617F and MPLnegative ET patients, thus leaving only a small cohort of triple-negative patients lacking a disease-causing genetic marker.…”

Section: Discussionsupporting

confidence: 74%

“…In a plethora of subsequent studies published within 3 months, the initial findings were confirmed and extended focusing on the clinical correlates. [10][11][12][13] Several additional studies described low frequencies of CALR mutations in different MPN-related diseases, but not in other hematologic diseases. 8,9,[14][15][16][17][18] As a result of the discovery of CALR mutations, definite molecular diagnostics have become available for 75-90% of clonal MPN.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Distinct clinical characteristics of myeloproliferative neoplasms with calreticulin mutations

et al. 2014

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Distinct clinical characteristics of myeloproliferative neoplasms with calreticulin mutations

et al. 2014

View full text Add to dashboard Cite

“…Polymerase-chainreaction (PCR) of DNA followed by Sanger sequencing or fragment size analysis have been used in the studies reported thus far and have a sensitivity of 5-10%. It is conceivable that more sensitive tests could be devised in the near future [8]. Whilst the two commonest CALR mutations (CALRdel52 and CALRins5) could theoretically be identified by a sensitive mutant allele-specific PCR method, such an assay would not identify about 15% of CALR mutated patients that carry infrequent variants, thus limiting their diagnostic utility.…”

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

confidence: 99%

CALR mutations in myeloproliferative neoplasms: Hidden behind the reticulum

et al. 2014

View full text Add to dashboard Cite

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...

show abstract

“…CALR exon 9 was amplified as described previously, with minor adaptations. 18,19 MPL exon 10 was amplified using either of the following primers: forward 5′-TAGGGGCTGGCTGGATG-3′ and reverse 5′-GGGGTCACAGAGCGAAC-3′ or forward 5′-CCGAAGTCTGACCCTTTTTG-3′ and reverse 5′-GACGGAGATCT GGGGTCAC-3′.…”

Section: Data Source and Patient Selectionmentioning

confidence: 99%

Effect of conditioning regimens on graft failure in myelofibrosis: a retrospective analysis

Slot

Smits

Donk

et al. 2015

Bone Marrow Transplant

View full text Add to dashboard Cite

In myelofibrosis, the introduction of reduced-intensity conditioning (RIC) preceding allogeneic stem cell transplantation (SCT) resulted in lower transplant-related mortality rates compared with myeloablative conditioning. However, lowering the intensity of conditioning may increase the risk of graft failure in myelofibrosis, although hitherto this has not been indisputably proven. We here report the outcome of 53 patients who underwent allogeneic SCT with different conditioning regimens (RIC and nonmyeloablative (NMA)) in three transplantation centers in the Netherlands. The cumulative incidence of graft failure within 60 days after SCT was high (28%), and this was primarily associated with the intensity of the conditioning regimen. Cumulative neutrophil engraftment at 60 days was lower in patients who received NMA conditioning compared with those who received RIC (56% vs 84%, P = 0.03). Furthermore, of six patients who received a second transplantation after graft failure, the three patients with RIC regimens subsequently engrafted, whereas the three patients who received a second NMA regimen did not. This study indicates that in myelofibrosis, NMA regimens result in high engraftment failure rates. We propose the use of more intensive conditioning regimens, incorporating busulfan or melphalan.

show abstract

Calreticulin gene exon 9 frameshift mutations in patients with thrombocytosis

Cited by 50 publications

References 15 publications

Distinct clinical characteristics of myeloproliferative neoplasms with calreticulin mutations

Distinct clinical characteristics of myeloproliferative neoplasms with calreticulin mutations

CALR mutations in myeloproliferative neoplasms: Hidden behind the reticulum

Effect of conditioning regimens on graft failure in myelofibrosis: a retrospective analysis

Contact Info

Product

Resources

About