Effects of CALR-Mutant Type and Burden on the Phenotype of Myeloproliferative Neoplasms

Kim, Sujeong; Han, Yujin; Jang, Jun Ho; Jung, Chul Won; Kim, Sun‐Hee; Kim, Hee‐Jin

doi:10.3390/diagnostics12112570

Cited by 7 publications

(5 citation statements)

References 22 publications

(55 reference statements)

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“…Indeed, mutant CALR is accountable for a gain-of-function property, triggering thrombopoietin receptor activation and downstream cellular signalling via the JAK-signal transducer and activator of transcription (JAK-STAT) pathway. Despite all of this evidence, making CALR one of the most important diagnostic markers tested upon diagnosis of a myeloproliferative disorder, our data suggest a milder disease in patients harbouring CALR mutations since it is related to higher platelet counts, lower haemoglobin levels, and leukocyte counts but a lower risk of thrombosis than patients with JAK2 and MPL mutations [31].…”

Section: Discussioncontrasting

confidence: 65%

Integrated Approach to Highlighting the Molecular Bases of a Deep Vein Thrombosis Event in an Elite Basketball Athlete

Mennitti,

Miele,

Scarano

et al. 2023

IJMS

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Acute or intense exercise can result in metabolic imbalances, muscle injuries, or reveal hidden disorders. Laboratory medicine in sports is playing an increasingly crucial role in monitoring athletes’ health conditions. In this study, we designed an integrated approach to explore the causes of a deep venous thrombosis event in an elite basketball player. Since the complete blood count revealed a marked platelet count (838 × 103 µL), and thrombophilia screening tests did not reveal any significant alteration, we evaluated the thrombin generation, which highlights a state of hypercoagulability. First-level haemostasis exams showed only a slight prolongation of the activated Partial Thromboplastin Time (aPTT). Thus, screening tests for von Willebrand Disease showed a reduction in vWF parameters. Therefore, we directed our hypothesis towards a diagnosis of acquired von Willebrand disease secondary to Essential Thrombocythemia (ET). To confirm this hypothesis and highlight the molecular mechanism underlying the observed phenotype, molecular tests were performed to evaluate the presence of the most common mutations associated with ET, revealing a 52-bp deletion in the coding region of CALR exon 9. This case report highlights the importance of an integrated approach to monitoring the athletes’ health status to personalise training and treatments, thus avoiding the appearance of diseases and injuries that, if underestimated, can undermine the athlete’s life.

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Section: Discussioncontrasting

confidence: 65%

Integrated Approach to Highlighting the Molecular Bases of a Deep Vein Thrombosis Event in an Elite Basketball Athlete

Mennitti,

Miele,

Scarano

et al. 2023

IJMS

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“…Notably, Guglielmelli et al recently found an association of high mutant CALR VAF (≥55%) with shorter anemia-free and leukocytosis-free survivals, and thereby, more aggressive disease compared to low CALR VAF (<55%) in a cohort of 620 patients who had PMF or secondary MF [ 75 ]. Interestingly, CALR type 2/type 2-like mutations were associated with higher median Hb levels, significantly higher platelet counts, and higher white blood cell counts compared to CALR type 1/type 1-like mutations in a small cohort of PMF patients [ 76 ]. TP53 mutations were enriched (19%) in patients who had secondary MF and ≥2 cytopenias ( p = 0.0024) [ 11 ].…”

Section: Genes Associated With the Myeloproliferative And Myelodeplet...mentioning

confidence: 99%

Association of Myelofibrosis Phenotypes with Clinical Manifestations, Molecular Profiles, and Treatments

Chifotides

Verstovšek

Bose

2023

Cancers

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Myelofibrosis (MF) presents an array of clinical manifestations and molecular profiles. The two distinct phenotypes− myeloproliferative and myelodepletive or cytopenic− are situated at the two poles of the disease spectrum and are largely defined by different degrees of cytopenias, splenomegaly, and distinct molecular profiles. The myeloproliferative phenotype is characterized by normal/higher peripheral blood counts or mildly decreased hemoglobin, progressive splenomegaly, and constitutional symptoms. The myeloproliferative phenotype is typically associated with secondary MF, higher JAK2 V617F burden, fewer mutations, and superior overall survival (OS). The myelodepletive phenotype is usually associated with primary MF, ≥2 cytopenias, modest splenomegaly, lower JAK2 V617F burden, higher fibrosis, greater genomic complexity, and inferior OS. Cytopenias are associated with mutations in epigenetic regulators/splicing factors, clonal evolution, disease progression, and shorter OS. Clinical variables, in conjunction with the molecular profiles, inform integrated prognostication and disease management. Ruxolitinib/fedratinib and pacritinib/momelotinib may be more suitable to treat patients with the myeloproliferative and myelodepletive phenotypes, respectively. Appreciation of MF heterogeneity and two distinct phenotypes, the different clinical manifestations and molecular profiles associated with each phenotype alongside the growing treatment expertise, the development of non-myelosuppressive JAK inhibitors, and integrated prognostication are leading to a new era in patient management. Physicians can increasingly tailor personalized treatments that will address the unique unmet needs of MF patients, including those presenting with the myelodepletive phenotype, to elicit optimal outcomes and extended OS across the disease spectrum.

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“…They have found that in patients with type 1-like CALR mutation, CALR mutant burden was negatively correlated with the hemoglobin level and platelet count, whereas CALR mutant burden was positively correlated with absolute neutrophil count and platelet count with type 2-like CALR-mutated patients. Nevertheless, the study was conducted on a small number of patients (Kim et al, 2022). There are several methods for detecting the CALR mutation.…”

Section: Figurementioning

confidence: 99%

BCR::ABL1-negative myeloproliferative neoplasms in the era of next-generation sequencing

Mroczkowska-Bękarciak,

Wróbel

2023

Front. Genet.

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The classical BCR::ABL1-negative myeloproliferative neoplasms such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal diseases with the presence of characteristic “driver mutations” in one of the genes: JAK2, CALR, or MPL. The search for mutations in these three genes is required for the diagnosis of MPNs. Nevertheless, the progress that has been made in the field of molecular genetics has opened a new era in medicine. The search for additional mutations in MPNs is helpful in assessing the risk stratification, disease progression, transformation to acute myeloid leukemia (AML), or choosing the right treatment. In some cases, advanced technologies are needed to find a clonal marker of the disease and establish a diagnosis. This review focuses on how the use of new technologies like next-generation sequencing (NGS) helps in the diagnosis of BCR::ABL1-negative myeloproliferative neoplasms.

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Effects of CALR-Mutant Type and Burden on the Phenotype of Myeloproliferative Neoplasms

Cited by 7 publications

References 22 publications

Integrated Approach to Highlighting the Molecular Bases of a Deep Vein Thrombosis Event in an Elite Basketball Athlete

Integrated Approach to Highlighting the Molecular Bases of a Deep Vein Thrombosis Event in an Elite Basketball Athlete

Association of Myelofibrosis Phenotypes with Clinical Manifestations, Molecular Profiles, and Treatments

BCR::ABL1-negative myeloproliferative neoplasms in the era of next-generation sequencing

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