Nagata Y.,Kyoto University |
Kontani K.,Kyoto University |
Enami T.,University of Tokyo |
Kataoka K.,University of Tokyo |
And 32 more authors.
Blood | Year: 2016
AdultT-cell leukemia/lymphoma(ATLL) isadistinct formofperipheral T-cell lymphomawith poor prognosis, which is caused by the human T-lymphotropic virus type 1 (HTLV-1). In contrast to theunequivocal importanceofHTLV-1infectioninthepathogenesisofATLL, the role of acquired mutations in HTLV-1 infected T cells has not been fully elucidated, with a handful of genes known to be recurrentlymutated. In this study,we identifieduniqueRHOA mutations in ATLL through whole genome sequencing of an index case, followed by deep sequencing of 203 ATLL samples. RHOA mutations showed distinct distribution and function from those found in other cancers. Involving 15% (30/203) of ATLL cases, RHOA mutations werewidely distributed across the entire coding sequence but almost invariably located at the guanosine triphosphate (GTP)-binding pocket, with Cys16Arg being most frequently observed. Unexpectedly, depending on mutation types and positions, these RHOA mutants showed different or even opposite functional consequences in terms of GTP/guanosine diphosphate (GDP)-binding kinetics, regulation of actin fibers, and transcriptional activation. TheGly17Val mutant did not bind GTP/GDP and act as a dominant negativemolecule, whereas othermutants (Cys16Arg and Ala161Pro) showed fast GTP/GDP cycling with enhanced transcriptional activation. These findings suggest that both loss-And gain-of-RHOA functions could be involved in ATLL leukemogenesis. In summary, our study not only provides a novel insight into the molecular pathogenesis of ATLL but also highlights a unique role of variegation of heterologous RHOA mutations in human cancers. © 2016 by The American Society of Hematology. Source
Tsujita Y.,National Defense Medical College |
Mitsui-Sekinaka K.,National Defense Medical College |
Imai K.,National Defense Medical College |
Yeh T.-W.,Tokyo Medical and Dental University |
And 30 more authors.
Journal of Allergy and Clinical Immunology | Year: 2016
Background: Activated phosphatidylinositol 3-kinase δ syndrome (APDS) is a recently discovered primary immunodeficiency disease (PID). Excess phosphatidylinositol 3-kinase (PI3K) activity linked to mutations in 2 PI3K genes, . PIK3CD and . PIK3R1, causes APDS through hyperphosphorylation of AKT, mammalian target of rapamycin (mTOR), and S6. Objective: This study aimed to identify novel genes responsible for APDS. Methods: Whole-exome sequencing was performed in Japanese patients with PIDs. Immunophenotype was assessed through flow cytometry. Hyperphosphorylation of AKT, mTOR, and S6 in lymphocytes was examined through immunoblotting, flow cytometry, and multiplex assays. Results: We identified heterozygous mutations of phosphatase and tensin homolog . (PTEN) in patients with PIDs. Immunoblotting and quantitative PCR analyses indicated that . PTEN expression was decreased in these patients. Patients with . PTEN mutations and those with . PIK3CD mutations, including a novel E525A mutation, were further analyzed. The clinical symptoms and immunologic defects of patients with . PTEN mutations, including lymphocytic AKT, mTOR, and S6 hyperphosphorylation, resemble those of patients with APDS. Because PTEN is known to suppress the PI3K pathway, it is likely that defective PTEN results in activation of the PI3K pathway. Conclusion: . PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes. © 2016 American Academy of Allergy, Asthma & Immunology. Source
Damm F.,French Institute of Health and Medical Research |
Damm F.,Institute Gustave Roussy |
Mylonas E.,French Institute of Health and Medical Research |
Mylonas E.,Institute Gustave Roussy |
And 56 more authors.
Cancer Discovery | Year: 2014
Appropriate cancer care requires a thorough understanding of the natural history of the disease, including the cell of origin, the pattern of clonal evolution, and the functional consequences of the mutations. Using deep sequencing of flow-sorted cell populations from patients with chronic lymphocytic leukemia (CLL), we established the presence of acquired mutations in multipotent hematopoietic progenitors. Mutations affected known lymphoid oncogenes, including BRAF, NOTCH1, and SF3B1. NFKBIE and EGR2 mutations were observed at unexpectedly high frequencies, 10.7% and 8.3% of 168 advanced-stage patients, respectively. EGR2 mutations were associated with a shorter time to treatment and poor overall survival. Analyses of BRAF and EGR2 mutations suggest that they result in deregulation of B-cell receptor (BCR) intracellular signaling. Our data propose disruption of hematopoietic and early B-cell differentiation through the deregulation of pre-BCR signaling as a phenotypic outcome of CLL mutations and show that CLL develops from a pre-leukemic phase. SIGNIFICANCE: The origin and pathogenic mechanisms of CLL are not fully understood. The current work indicates that CLL develops from pre-leukemic multipotent hematopoietic progenitors carrying somatic mutations. It advocates for abnormalities in early B-cell differentiation as a phenotypic convergence of the diverse acquired mutations observed in CLL. © 2014 American Association for Cancer Research. Source
Seki M.,University of Tokyo |
Yoshida K.,Cancer Genomics Project |
Yoshida K.,Kyoto University |
Shiraishi Y.,Laboratory of DNA Information Analysis |
And 23 more authors.
Cancer Research | Year: 2014
Pleuropulmonary blastoma (PPB) is a rare pediatric malignancy whose pathogens are poorly understood. Recent reports suggest that germline mutations in the microRNA-processing enzyme DICER1 may contribute to PPB development. To investigate the genetic basis of this cancer, we performed whole-exome sequencing or targeted deep sequencing of multiple cases of PPB. We found biallelic DICER1 mutations to be very common, more common than TP53 mutations also found in many tumors. Somatic ribonuclease III (RNase IIIb) domain mutations were identified in all evaluable cases, either in the presence or absence of nonsense/frameshift mutations. Most cases had mutated DICER1 alleles in the germline with or without an additional somatic mutation in the remaining allele, whereas other cases displayed somatic mutations exclusively where the RNase IIIb domain was invariably affected. Our results highlight the role of RNase IIIb domain mutations in DICER1 along with TP53 inactivation in PPB pathogenesis. © 2014 American Association for Cancer Research. Source