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Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia.

ABSTRACT: 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.

SUBMITTER: Radjasandirane R

PROVIDER: S-EPMC10046389 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia.

Radjasandirane Ragousandirane R de Brevern Alexandre G AG

Biomolecules 20230310 3

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. ...[more]

PMID: 36979444

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Project description:Essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (pre-PMF) are Philadelphia chromosome-negative myeloproliferative neoplasms. These conditions share overlapping clinical presentations; however, their prognoses differ significantly. Current morphological diagnostic methods lack reliability in subtype differentiation, underlining the need for improved diagnostics. The aim of this study was to investigate the multi-omics alterations in bone marrow biopsies of patients with ET and pre-PMF to improve our understanding of the nuanced diagnostic characteristics of both diseases. We performed proteomic analysis with 4D direct data-independent acquisition and microbiome analysis with 2bRAD-M sequencing technology to identify differential protein and microbe levels between untreated patients with ET and pre-PMF. Laboratory and multi-omics differences were observed between ET and pre-PMF, encompassing diverse pathways, such as lipid metabolism and immune response. The pre-PMF group showed an increased neutrophil-to-lymphocyte ratio and decreased high-density lipoprotein and cholesterol levels. Protein analysis revealed significantly higher CXCR2, CXCR4, and MX1 levels in pre-PMF, while APOC3, APOA4, FABP4, C5, and CFB levels were elevated in ET, with diagnostic accuracy indicated by AUC values ranging from 0.786 to 0.881. Microbiome assessment identified increased levels of Mycobacterium, Xanthobacter, and L1I39 in pre-PMF, whereas Sphingomonas, Brevibacillus, and Pseudomonas_E were significantly decreased, with AUCs for these genera ranging from 0.833 to 0.929. Our study provides preliminary insights into the proteomic and microbiome variations in the bone marrow of patients with ET and pre-PMF, identifying specific proteins and bacterial genera that warrant further investigation as potential diagnostic indicators. These observations contribute to our evolving understanding of the multi-omics variations and possible mechanisms underlying ET and pre-PMF.

Dataset Information

Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia.

Publications

Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia.

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