Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms

Klampfl, Thorsten; Gisslinger, Heinz; Harutyunyan, Ashot S.; Nivarthi, Harini; Rumi, Elisa; Milosevic, Jelena D.; Them, Nicole C.C.; Berg, Tiina; Gisslinger, Bettina; Pietra, Daniela; Chen, Doris; Vladimer, Gregory I.; Bagienski, Klaudia; Milanesi, Chiara; Casetti, Ilaria Carola; Sant’Antonio, Emanuela; Ferretti, Virginia Valeria; Elena, Chiara; Schischlik, Fiorella; Cleary, Ciara; Six, Melanie; Schalling, Martin; Schönegger, Andreas; Bock, Christoph; Malcovati, Luca; Pascutto, Cristiana; Superti‐Furga, Giulio; Cazzola, Mario; Královics, Róbert

doi:10.1056/nejmoa1311347

Cited by 1,771 publications

(2,155 citation statements)

References 31 publications

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“…PMF refers to BCR‐ABL1 ‐negative MPN, and is a clonal disorder of haematopoiesis arising in the haematopoietic stem cell (HSC) 2. The majority of patients with PMF carry mutations that activate JAK–STAT signalling; 60% harbour the JAK2V617F mutation, approximately 30% carry a calreticulin (CALR) mutation, and 8% carry a myeloproliferative leukaemia virus oncogene ( MPL ) mutation 3, 4, 5, 6, 7, 8. PMF is the most aggressive of the three classic MPNs, and is associated with significantly shortened survival 9, 10.…”

Section: Bone Marrow Fibrosismentioning

confidence: 99%

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

Gleitz

Kramann

Schneider

2018

The Journal of Pathology

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Bone marrow fibrosis is the continuous replacement of blood‐forming cells in the bone marrow with excessive scar tissue, leading to failure of the body to produce blood cells and ultimately to death. Myofibroblasts are fibrosis‐driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis have remained obscure. Recent work has demonstrated that Gli1+ and leptin receptor+ mesenchymal stromal cells are progenitors of fibrosis‐causing myofibroblasts in the bone marrow. Genetic ablation or pharmacological inhibition of Gli1+ mesenchymal stromal cells ameliorated fibrosis in mouse models of myelofibrosis. Conditional deletion of the platelet‐derived growth factor (PDGF) receptor‐α (PDGFRA) gene (Pdgfra) and inhibition of PDGFRA by imatinib in leptin receptor+ stromal cells suppressed their expansion and ameliorated bone marrow fibrosis. Understanding the cellular and molecular mechanisms in the haematopoietic stem cell niche that govern the mesenchymal stromal cell‐to‐myofibroblast transition and myofibroblast expansion will be critical to understand the pathogenesis of bone marrow fibrosis in both malignant and non‐malignant conditions, and will guide the development of novel therapeutics. In this review, we summarize recent discoveries of mesenchymal stromal cells as part of the haematopoietic niche and as myofibroblast precursors, and discuss potential therapeutic strategies in the specific targeting of fibrotic transformation in bone marrow fibrosis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Bone Marrow Fibrosismentioning

confidence: 99%

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

Gleitz

Kramann

Schneider

2018

The Journal of Pathology

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“…24 Transfection of mutant CALR into a Ba/F3 murine cell line was shown to induce IL-3-independent growth that was associated with increased STAT5 phosphorylation. 6 However, the particular observation needs to be validated and further elaborated upon. Regardless, it is possible that a CALR, compared with a JAK2-mutated clone is genetically more stable and biologically more capable of handling the epigenetic alteration associated with mutant ASXL1.…”

Section: Calr-asxl1+mentioning

confidence: 99%

“…4 JAK2 or MPL mutations are found in 50-70% of patients with PMF or essential thrombocythemia (ET) and calreticulin (CALR) mutations account for the majority of the remaining cases; 5,6 in strictly World Health Organization-defined disease, CALR mutations were seen in 49% of ET and 74% of PMF patients not expressing mutant JAK2 or MPL. 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.…”

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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“…The "black box" that comprised 40% of ET and PMF patients lacking a recurrent genetic marker of disease has now largely been resolved by the discovery of mutations in the gene Calreticulin (CALR) reported independently by the research groups of Tony Green/Peter Campbell [2] and Robert Kralovics [3]. Both studies employed exome sequencing of matched tumor and germline DNA, followed by targeted resequencing in larger cohorts, to identify recurrent mutations in CALR in 60-88% of patients with ET and PMF who were negative for JAK2 and MPL mutations.…”

Section: Calreticulin Mutations In Mpn: Filling the Gapmentioning

confidence: 99%

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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Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms

Cited by 1,771 publications

References 31 publications

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

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

CALR mutations in myeloproliferative neoplasms: Hidden behind the reticulum

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