55 research outputs found
Cell cycle synchronization and BrdU incorporation as a tool to study the possible selective elimination of ErbB1 gene in the micronuclei in A549 cells
Progress towards molecular-based management of childhood Langerhans cell histiocytosis
International audienceLangerhans cell histiocytosis (LCH) is characterized by inflammatory lesions containing abundant CD1a+ CD207+ histiocytes that lead to the destruction of affected tissues. This disease has a remarkable pleiotropic clinical presentation and most commonly affects young children. Although the current mortality rate is very low for childhood LCH patients (<2%), reactivation frequently occurs after a long period of disease control and the rates of permanent complications and sequelae remain high. Advances in genomic sequencing technologies in this past decade have highlighted somatic molecular alterations responsible for the disease in around 80% of childhood LCH cases. More than half of these cases harbored the BRAFV600E mutation, and most other mutations also concerned proteins involved in the MAPKinase pathway. In addition to improving what is known about the LCH pathology, this molecular knowledge provides opportunities to optimize patient management. The BRAFV600E mutation is associated with more severe presentations of the disease, a high reactivation rate, and a high permanent complication rate; this mutation therefore paves the way for future stratified management approaches. These therapies may be based on the patient's molecular status as well as other clinical characteristics of the disease that are independently associated with undesired events. Moreover, as observed in patients with solid tumors, the BRAFV600E allele can be detected in the circulating cell-free DNA of patients with severe BRAFV600E-mutated LCH. Quantification of the plasmatic BRAFV600E load for this group of patients can precisely monitor response to therapy. Finally, targeted therapies, such as BRAF inhibitors, are new therapeutic options especially designed for refractory multisystemic LCH involving risk organs. However, the long-term efficacy, long-term tolerance, optimal protocol scheme, and appropriate modalities of administration for these innovative therapies for children still need to be defined, a huge challenge
Progress towards molecular-based management of childhood Langerhans cell histiocytosis
International audienceLangerhans cell histiocytosis (LCH) is characterized by inflammatory lesions containing abundant CD1a+ CD207+ histiocytes that lead to the destruction of affected tissues. This disease has a remarkable pleiotropic clinical presentation and most commonly affects young children. Although the current mortality rate is very low for childhood LCH patients (<2%), reactivation frequently occurs after a long period of disease control and the rates of permanent complications and sequelae remain high. Advances in genomic sequencing technologies in this past decade have highlighted somatic molecular alterations responsible for the disease in around 80% of childhood LCH cases. More than half of these cases harbored the BRAFV600E mutation, and most other mutations also concerned proteins involved in the MAPKinase pathway. In addition to improving what is known about the LCH pathology, this molecular knowledge provides opportunities to optimize patient management. The BRAFV600E mutation is associated with more severe presentations of the disease, a high reactivation rate, and a high permanent complication rate; this mutation therefore paves the way for future stratified management approaches. These therapies may be based on the patient's molecular status as well as other clinical characteristics of the disease that are independently associated with undesired events. Moreover, as observed in patients with solid tumors, the BRAFV600E allele can be detected in the circulating cell-free DNA of patients with severe BRAFV600E-mutated LCH. Quantification of the plasmatic BRAFV600E load for this group of patients can precisely monitor response to therapy. Finally, targeted therapies, such as BRAF inhibitors, are new therapeutic options especially designed for refractory multisystemic LCH involving risk organs. However, the long-term efficacy, long-term tolerance, optimal protocol scheme, and appropriate modalities of administration for these innovative therapies for children still need to be defined, a huge challenge
Selective elimination of amplified CDK4 sequences correlates with spontaneous adipocytic differentiation in liposarcoma.
International audienceWell-differentiated and undifferentiated liposarcomas are characterized by high-level amplifications of chromosome 12 regions including the CDK4 and MDM2 genes. These amplicons are either localized, in well-differentiated liposarcoma (WDLPS), on extrachromosomal structures (ring or rod chromosomes), or integrated into chromosome arms in undifferentiated tumors. Our results reveal that extrachromosomal amplicons are unstable, and frequently lost by micronucleation. This loss correlates with hypermethylation of eliminated sequences and changes of their replication time. Treatment of cells with demethylating agents during early S-phase significantly decreases the rate of micronuclei positive for CDK4. We also demonstrate that, in our model, micronuclei are generated during anaphase as a consequence of anaphase abnormalities (chromosome lagging and anaphase bridges). Finally, a dramatic increase of adipocytic differentiation was noted in cells that have eliminated copies of CDK4 gene in micronuclei. These findings provide evidence that, in WDLPS, adipocytic differentiation could be the consequence of CDK4 loss, an event occurring rarely in undifferentiated tumors in which the amplified sequences are integrated into chromosome arms
Reply to “Clinical and therapeutic implications of BRAF mutation heterogeneity in metastatic melanoma” by Mesbah Ardakani et al.
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A circulating subset of BRAFV600E-positive cells in infants with high-risk Langerhans cell histiocytosis treated with BRAF inhibitors
International audienceBRAF inhibitors are an effective treatment for BRAFV600E-mutated, risk-organ-positive Langerhans cell histiocytosis (RO+ LCH). However, cell-free BRAFV600E DNA often persists during therapy and recurrence frequently occurs after therapy discontinuation. To identify a pathological reservoir of BRAFV600E-mutated cells, we studied peripheral blood cells obtained from six infants with RO+ multisystem (MS) LCH that received targeted therapy. After cell sorting, the BRAFV600E mutation was detected in monocytes (n = 5), B lymphocytes (n = 3), T lymphocytes (n = 2), and myeloid and plasmacytoid dendritic cells (n = 2 each). This biomarker may offer an interesting tool for monitoring the effectiveness of new therapeutic approaches for weaning children with RO+ LCH from targeted therapy
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