Phenotypic correlations of CALR mutation variant allele frequency in patients with myelofibrosis

Guglielmelli, Paola; Maccari, Chiara; Sordi, Benedetta; Balliu, Manjola; Atanasio, Alessandro; Mannarelli, Carmela; Capecchi, Giulio; Sestini, Ilaria; Coltro, Giacomo; Loscocco, Giuseppe Gaetano; Rotunno, Giada; Angori, Eva; Borri, Filippo C.; Tefferi, Ayalew; Vannucchi, Alessandro M.

doi:10.1038/s41408-023-00786-x

Cited by 12 publications

(13 citation statements)

References 15 publications

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“…Nevertheless, the suggestion that HMR VAF modifies the prognostic contribution of HMR mutations in MF is an important one that warrants additional studies. Consistently, previous reports have also suggested prognostic relevance of MPN-driver mutation VAF in MF (CALR), 28 PV (JAK2), 29 and ET (CALR). 30 Risk models in MF are mostly needed for treatment decision making but can also predict post-transplant survival.…”

supporting

confidence: 88%

Risk models in myelofibrosis—the past, present, and future

Tefferi,

Vannucchi

2024

American J Hematol

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supporting

confidence: 88%

Risk models in myelofibrosis—the past, present, and future

Tefferi,

Vannucchi

2024

American J Hematol

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“…It has been observed that MF with CALR type-1 mutation showed longer survival than those with type-2 mutation [26,27]. In addition, shorter survival and anemia were associated with higher CALR VAF in a study including 121 patients with CALR-mutated MF, suggesting a more advanced disease [28]. However, high VAF CALR-mutated patients were significantly enriched with ASXL1 mutations indicating that patients with high CALR VAF mostly corresponded to MF with chromatin/spliceosome mutations.…”

Section: Discussionmentioning

confidence: 98%

Clinical Characteristics and Outcomes of Patients with Primary and Secondary Myelofibrosis According to the Genomic Classification Using Targeted Next-Generation Sequencing

Garrote

López‐Guerra

Arellano‐Rodrigo

et al. 2023

Cancers

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Myelofibrosis (MF) is a heterogeneous disease regarding its mutational landscape, clinical presentation, and outcomes. The aim of our work is to evaluate the genomic classification of MF considering whether it is primary or secondary. One-hundred seventy-five patients, 81 with primary MF (PMF) and 94 with secondary MF (SMF) were hierarchically allocated into eight molecular groups. We found that TP53 disruption/aneuploidy (n = 16, 9%) was more frequent (12% versus 6%) and showed higher allele burden (57% versus 15%, p = 0.01) in SMF than in PMF, and was associated with shorter survival (median 3.5 years). Mutations in chromatin/spliceosome genes (n = 72, 41%) represented the most frequent genomic group in PMF. Homozygous JAK2 mutation (n = 40, 23%) was enriched with old patients with SMF after long-standing polycythemia vera, whereas MF with heterozygous JAK2 mutation (n = 22, 13%) was similarly distributed among PMF and SMF. MF with CALR mutation (n = 19, 11%) predominated in post-essential thrombocythemia MF. The remaining genomic groups were infrequent. TP53 disruption, chromatin/spliceosome mutation, and homozygous JAK2 mutation were associated with significantly shorter survival and higher risk of progression. In conclusion, genomic classification reveals different pathogenic pathways between PMF and SMF and provides relevant information regarding disease phenotype and outcomes.

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“…These results are important as ET is associated with a large number of complications [ 9 ], and it remains difficult to associate the clinical significance with the prognoses of the different CALR types [ 90 , 91 ]. Herein, we underlined that these types must also be carefully taken into consideration.…”

Section: Discussionmentioning

confidence: 99%

Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia

Radjasandirane

Brevern

2023

Biomolecules

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Essential thrombocythemia (ET) is a blood cancer. ET is characterized by an overproduction of platelets that can lead to thrombosis formation. Platelet overproduction occurs in megakaryocytes through a signaling pathway that could involve JAK2, MPL, or CALR proteins. CALR mutations are associated with 25–30% of ET patients; CALR variants must be dimerized to induce ET. We classified these variants into five classes named A to E; classes A and B are the most frequent classes in patients with ET. The dynamic properties of these five classes using structural models of CALR’s C-domain were analyzed using molecular dynamics simulations. Classes A, B, and C are associated with frameshifts in the C-domain. Their dimers can be stable only if a disulfide bond is formed; otherwise, the two monomers repulse each other. Classes D and E cannot be stable as dimers due to the absence of disulfide bonds. Class E and wild-type CALR have similar dynamic properties. These results suggest that the disulfide bond newly formed in classes A, B, and C may be essential for the pathogenicity of these variants. They also underline that class E cannot be directly related to ET but corresponds to human polymorphisms.

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Phenotypic correlations of CALR mutation variant allele frequency in patients with myelofibrosis

Cited by 12 publications

References 15 publications

Risk models in myelofibrosis—the past, present, and future

Risk models in myelofibrosis—the past, present, and future

Clinical Characteristics and Outcomes of Patients with Primary and Secondary Myelofibrosis According to the Genomic Classification Using Targeted Next-Generation Sequencing

Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia

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