Sequential evaluation of <i>CALR</i> mutant burden in patients with myeloproliferative neoplasms

Cavalloni, Chiara; Rumi, Elisa; Pietra, Daniela; Roncoroni, Elisa; Bellini, Marta; Ciboddo, Michele; Casetti, Ilaria Carola; Landini, Benedetta; Fugazza, Elena; Troletti, Daniela; Astori, Cesare; Cazzola, Mario

doi:10.18632/oncotarget.16797

Cited by 8 publications

(4 citation statements)

References 16 publications

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“…Anyway, 19pLOH appears to be a relatively uncommon event [ 37 ], in contrast with 9pLOH in JAK2 -mutant MPN and 1pLOH in MPL -mutant MPN [ 8 , 38 , 39 ]. It has been suggested that the clonal expansion in CALR -mutant MPN is faster than that observed in JAK2 -mutant MPN [ 40 ].…”

Section: Mutation and Clinical Phenotypementioning

confidence: 99%

The Genetic Basis of Primary Myelofibrosis and Its Clinical Relevance

Rumi

Trotti

Vanni

et al. 2020

IJMS

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Among classical BCR-ABL-negative myeloproliferative neoplasms (MPN), primary myelofibrosis (PMF) is the most aggressive subtype from a clinical standpoint, posing a great challenge to clinicians. Whilst the biological consequences of the three MPN driver gene mutations (JAK2, CALR, and MPL) have been well described, recent data has shed light on the complex and dynamic structure of PMF, that involves competing disease subclones, sequentially acquired genomic events, mostly in genes that are recurrently mutated in several myeloid neoplasms and in clonal hematopoiesis, and biological interactions between clonal hematopoietic stem cells and abnormal bone marrow niches. These observations may contribute to explain the wide heterogeneity in patients’ clinical presentation and prognosis, and support the recent effort to include molecular information in prognostic scoring systems used for therapeutic decision-making, leading to promising clinical translation. In this review, we aim to address the topic of PMF molecular genetics, focusing on four questions: (1) what is the role of mutations on disease pathogenesis? (2) what is their impact on patients’ clinical phenotype? (3) how do we integrate gene mutations in the risk stratification process? (4) how do we take advantage of molecular genetics when it comes to treatment decisions?

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Section: Mutation and Clinical Phenotypementioning

confidence: 99%

The Genetic Basis of Primary Myelofibrosis and Its Clinical Relevance

Rumi

Trotti

Vanni

et al. 2020

IJMS

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“…47–50 CALR mutations appear to confer a greater proliferative advantage to the neoplastic clone compared with JAK2 mutations; clonal expansion is faster in CALR -mutated cases than in JAK2 -mutated cases, both in ET and in PMF. 51…”

Section: Essential Thrombocythemia: State Of the Art Updatementioning

confidence: 99%

SOHO State-of-the-Art Update and Next Questions: MPN

Bose

Gotlib

Harrison

et al. 2018

Clinical Lymphoma Myeloma and Leukemia

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The discovery of the activating Janus kinase (JAK)2 mutation in 2005 in most patients with the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) spurred intense interest in research into these disorders, culminating in the identification of activating mutations in MPL in 2006 and indels in the gene encoding calreticulin (CALR) in 2013, thus providing additional mechanistic explanations for the universal activation of JAK-signal transducer and activator of transcription (JAK-STAT) observed in these conditions, and the success of the JAK1/2 inhibitor ruxolitinib, which first received regulatory approval in 2011. The field has continued to advance rapidly since then, and the past 2 years have witnessed important changes to the classification of MPN and diagnostic criteria for polycythemia vera (PV), novel insights into the mechanisms of bone marrow fibrosis in primary myelofibrosis (PMF), increasing appreciation of the biologic differences between essential thrombocythemia (ET), prefibrotic and overt PMF, and between primary and post-PV/ET myelofibrosis (MF). Additionally, the mechanisms through which mutant CALR drives JAK-STAT pathway activation and oncogenic transformation are now better understood. Although mastocytosis is no longer included under the broad heading of MPN in the 2016 revision to the World Health Organization classification, an important milestone in mastocytosis research was reached in 2017 with the regulatory approval of midostaurin for patients with advanced systemic mastocytosis (AdvSM). In this article, we review the major recent developments in the areas of PV, ET, and MF, and also briefly summarize the literature on midostaurin and other KIT inhibitors for patients with AdvSM.

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“…The mutations all share the characteristic of affecting the JAK‐STAT signal transduction pathway generating the classic MPN phenotype, with activation and proliferation of the haematopoietic progenitor cell, and uncontrolled production of different terminal blood cell quantities, depending on MPN subtype and mutation type (Shallis et al, 2020 ). In the JAK2 and CALR positive, a steady increase in the mutational allele burden (“tumour” burden) is seen over the biological continuum for MPNs from the early‐stage disease to the advanced burned out PMF stage (Cavalloni et al, 2017 ; Hasselbalch, 2013 ).…”

Section: Introductionmentioning

confidence: 99%