scholarly journals Clinical and biological characterization of MPN patients harboring two driver mutations, a French intergroup of myeloproliferative neoplasms (FIM) study

2018 ◽  
Vol 93 (4) ◽  
pp. E84-E86 ◽  
Author(s):  
Olivier Mansier ◽  
Damien Luque Paz ◽  
Jean-Christophe Ianotto ◽  
Yannick Le Bris ◽  
Aurélie Chauveau ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Driver Mutations ◽  
Biological Characterization

scholarly journals Chronic Eosinophilic Leukaemia Associated with JAK2 Exon 13 Insertion/Deletion Mutations

2021 ◽  
pp. 1-6
Author(s):  
Nicholas Lafferty ◽  
Matthew Salmon ◽  
Nicholas C.P. Cross ◽  
Iain Singer ◽  
Aaron Cooney ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Driver Mutations ◽  
Rare Mutation ◽  
Indel Mutation ◽  
Not Otherwise Specified ◽  
Disease Subtypes ◽  
Specific Association ◽  
Eosinophilic Disorders ◽  
Made In

Chronic eosinophilic leukaemia, not otherwise specified (CEL, NOS), is a diagnosis of exclusion made in cases in which there is clonal eosinophilia but an absence of genetic aberrations that define other disease subtypes. There is a need for further characterization of these cases in order to inform risk stratification and management. The importance of <i>JAK2</i> mutations in myeloproliferative neoplasms (MPN) as a whole is well established, although their role specifically in eosinophilic disorders is less clear, with only a minority of cases demonstrating <i>JAK2</i> abnormalities. Here, we report 2 cases with an exon 13 insertion-deletion (indel) mutation in <i>JAK2:</i> one with CEL-NOS and the second with an unspecified eosinophilic disorder. <i>JAK2</i> indels were not detected in a screen of suspected MPN cases (<i>n</i> = 592) without eosinophilia that tested negative for common MPN driver mutations. Our findings thus provide further evidence for a specific association between this rare mutation and clonal eosinophilic disorders.

Targeting IDH Mutations in AML: Wielding the Double-edged Sword of Differentiation

2020 ◽  
Vol 20 (7) ◽  
pp. 490-500 ◽  
Author(s):  
Justin S. Becker ◽  
Amir T. Fathi
Keyword(s):  
Genome Structure ◽  
Cellular Metabolism ◽  
Standard Of Care ◽  
Competitive Inhibitor ◽  
Driver Mutations ◽  
New Class ◽  
Regulatory Enzymes ◽  
Idh Mutations ◽  
Genomic Characterization

The genomic characterization of acute myeloid leukemia (AML) by DNA sequencing has illuminated subclasses of the disease, with distinct driver mutations, that might be responsive to targeted therapies. Approximately 15-23% of AML genomes harbor mutations in one of two isoforms of isocitrate dehydrogenase (IDH1 or IDH2). These enzymes are constitutive mediators of basic cellular metabolism, but their mutated forms in cancer synthesize an abnormal metabolite, 2- hydroxyglutarate, that in turn acts as a competitive inhibitor of multiple gene regulatory enzymes. As a result, leukemic IDH mutations cause changes in genome structure and gene activity, culminating in an arrest of normal myeloid differentiation. These discoveries have motivated the development of a new class of selective small molecules with the ability to inhibit the mutant IDH enzymes while sparing normal cellular metabolism. These agents have shown promising anti-leukemic activity in animal models and early clinical trials, and are now entering Phase 3 study. This review will focus on the growing preclinical and clinical data evaluating IDH inhibitors for the treatment of IDH-mutated AML. These data suggest that inducing cellular differentiation is central to the mechanism of clinical efficacy for IDH inhibitors, while also mediating toxicity for patients who experience IDH Differentiation Syndrome. Ongoing trials are studying the efficacy of IDH inhibitors in combination with other AML therapies, both to evaluate potential synergistic combinations as well as to identify the appropriate place for IDH inhibitors within existing standard-of-care regimens.

scholarly journals Clonal approaches to understanding the impact of mutations on hematologic disease development

Blood ◽  
2019 ◽  
Vol 133 (13) ◽  
pp. 1436-1445 ◽  
Author(s):  
Jyoti Nangalia ◽  
Emily Mitchell ◽  
Anthony R. Green
Keyword(s):  
Somatic Mutations ◽  
Clonal Selection ◽  
Single Cells ◽  
Driver Mutations ◽  
Great Promise ◽  
Tumor Evolution ◽  
Disease Development ◽  
Hematopoietic Tissue ◽  
The Impact

Abstract Interrogation of hematopoietic tissue at the clonal level has a rich history spanning over 50 years, and has provided critical insights into both normal and malignant hematopoiesis. Characterization of chromosomes identified some of the first genetic links to cancer with the discovery of chromosomal translocations in association with many hematological neoplasms. The unique accessibility of hematopoietic tissue and the ability to clonally expand hematopoietic progenitors in vitro has provided fundamental insights into the cellular hierarchy of normal hematopoiesis, as well as the functional impact of driver mutations in disease. Transplantation assays in murine models have enabled cellular assessment of the functional consequences of somatic mutations in vivo. Most recently, next-generation sequencing–based assays have shown great promise in allowing multi-“omic” characterization of single cells. Here, we review how clonal approaches have advanced our understanding of disease development, focusing on the acquisition of somatic mutations, clonal selection, driver mutation cooperation, and tumor evolution.

scholarly journals Non-Coding Variants in Cancer: Mechanistic Insights and Clinical Potential for Personalized Medicine

2021 ◽  
Vol 7 (3) ◽  
pp. 47
Author(s):  
Marios Lange ◽  
Rodiola Begolli ◽  
Antonis Giakountis
Keyword(s):  
Disease Onset ◽  
Cancer Genome ◽  
Driver Mutations ◽  
Nucleotide Polymorphisms ◽  
Structural Variations ◽  
Coding Regions ◽  
Functional Variants ◽  
Coding Variants ◽  
Clinical Potential

The cancer genome is characterized by extensive variability, in the form of Single Nucleotide Polymorphisms (SNPs) or structural variations such as Copy Number Alterations (CNAs) across wider genomic areas. At the molecular level, most SNPs and/or CNAs reside in non-coding sequences, ultimately affecting the regulation of oncogenes and/or tumor-suppressors in a cancer-specific manner. Notably, inherited non-coding variants can predispose for cancer decades prior to disease onset. Furthermore, accumulation of additional non-coding driver mutations during progression of the disease, gives rise to genomic instability, acting as the driving force of neoplastic development and malignant evolution. Therefore, detection and characterization of such mutations can improve risk assessment for healthy carriers and expand the diagnostic and therapeutic toolbox for the patient. This review focuses on functional variants that reside in transcribed or not transcribed non-coding regions of the cancer genome and presents a collection of appropriate state-of-the-art methodologies to study them.

Identification, molecular and biological characterization of two novel secovirids in wild grass species in Belgium

2021 ◽  
Vol 298 ◽  
pp. 198397
Author(s):  
François J. Maclot ◽  
Virginie Debue ◽  
Arnaud G. Blouin ◽  
Núria Fontdevila Pareta ◽  
Lucie Tamisier ◽  
...  
Keyword(s):  
Grass Species ◽  
Biological Characterization ◽  
Wild Grass
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