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Hospital de Órbigo, Spain

Palomero T.,Columbia University | Couronne L.,Columbia University | Khiabanian H.,Columbia University | Kim M.-Y.,Columbia University | And 22 more authors.
Nature Genetics | Year: 2014

Peripheral T cell lymphomas (PTCLs) are a heterogeneous and poorly understood group of non-Hodgkin lymphomas. Here we combined whole-exome sequencing of 12 tumor-normal DNA pairs, RNA sequencing analysis and targeted deep sequencing to identify new genetic alterations in PTCL transformation. These analyses identified highly recurrent epigenetic factor mutations in TET2, DNMT3A and IDH2 as well as a new highly prevalent RHOA mutation encoding a p.Gly17Val alteration present in 22 of 35 (67%) angioimmunoblastic T cell lymphoma (AITL) samples and in 8 of 44 (18%) PTCL, not otherwise specified (PTCL-NOS) samples. Mechanistically, the RHOA Gly17Val protein interferes with RHOA signaling in biochemical and cellular assays, an effect potentially mediated by the sequestration of activated guanine-exchange factor (GEF) proteins. In addition, we describe new and recurrent, albeit less frequent, genetic defects including mutations in FYN, ATM, B2M and CD58 implicating SRC signaling, impaired DNA damage response and escape from immune surveillance mechanisms in the pathogenesis of PTCL. © 2014 Nature America, Inc.


Navarro A.,Human Anatomy Unit | Diaz T.,Human Anatomy Unit | Cordeiro A.,Human Anatomy Unit | Beya M.D.,Hospital Clinic Barcelona | And 4 more authors.
Leukemia and Lymphoma | Year: 2015

Epigenetic mechanisms are crucial for the inactivation of key genes related to the survival of Hodgkin lymphoma (HL) cells, and methylation is a frequent epigenetic mechanism of microRNA silencing. We have examined the methylation-induced silencing of tumor suppressor microRNAs in HL cell lines and confirmed our results in patient lymph nodes. In addition, we evaluated the in vitro effectiveness of 5-aza-2-deoxycytidine (5-Aza-dC) in HL cell lines. Ten microRNAs containing CpG islands in their promoter region were re-expressed in both the L-428 and L-1236 cell lines. Interestingly, miR-34a and miR-203, both known tumor suppressor microRNAs, were found to be methylated in cell lines and in patient samples. 5-Aza-dC treatment resulted in a dose-dependent antiproliferative effect at 72 h in all the HL cell lines. In summary, 5-Aza-dC treatment of HL cell lines inhibits proliferation at high doses and produces re-expression of the tumor suppressor microRNAs at low-intermediate doses. © 2015 Informa UK, Ltd.


Pileri A.,University of Bologna | Bacci F.,Hematopathology Section | Neri I.,University of Bologna | Ciabatti S.,University of Bologna | And 3 more authors.
Dermatology | Year: 2012

Background: Persistent agmination of lymphomatoid papulosis (PALP) has been a matter of controversy in the literature, some authors suggesting that it represents composite lymphoma, others localized lymphomatoid papulosis (LyP). Patient and Methods: A 64-year-old man was referred to our outpatient center complaining of papular eruptions lasting 3 years. At physical examination, he showed papulonodular lesions on the trunk and extremities. Some patches on the trunk and upper arms were also observed. Both types of lesion were biopsied and studied on histological, immunohistochemical and molecular grounds. Results: The nodular lesion revealed the classical features of LyP type A, while the patch was characterized by the presence of a superficial and deep infiltrate with perivascular and interstitial location, consisting of mature lymphocytes admixed with plasma cells and large atypical cells that became more numerous beneath the epidermis. On immunohistochemistry the two lesions presented the same profile. Conclusion: Our case suggests that PALP does not correspond to localized LyP, as it can involve different skin areas since its presentation. Furthermore it rules out the possibility that PALP is a composite lymphoma. In fact, the same cytological and phenotypic characteristics were detected in all samples, including those taken from patchy areas. © 2012 S. Karger AG, Basel.


Pan Z.,Aurora University | Pan Z.,City of Hope Medical Center | Xie Q.,Hematopathology Section | Repertinger S.,Creighton University | And 3 more authors.
Human Pathology | Year: 2013

Plasmablastic transformation of low-grade B-cell lymphoproliferative disorders is rarely reported, particularly in cases with clonal evolution. Moreover, the relationship of these 2 morphologically and immunophenotypically distinctive neoplasms remains elusive. Here, we report 2 exceptional cases of plasmablastic transformation with apparently direct transformation from their preceding low-grade B-cell lymphoproliferative disorder. In both cases, the plasmablastic transformation and low-grade lymphoproliferative disorder shared the same immunoglobulin heavy chain gene rearrangements and an identical chromosomal translocation. Notably, both plasmablastic transformation cases also carried MYC gene rearrangements on chromosome 8q24, which have been frequently identified in de novo plasmablastic lymphoma. Therefore, our data suggest that dysregulation of MYC gene may play a critical role in the pathogenesis of plasmablastic transformation. © 2013 Elsevier Inc.


Giefing M.,University of Kiel | Giefing M.,Polish Academy of Sciences | Winoto-Morbach S.,University of Kiel | Sosna J.,University of Kiel | And 7 more authors.
PLoS ONE | Year: 2013

The membrane bound NADPH oxidase involved in the synthesis of reactive oxygen species (ROS) is a multi-protein enzyme encoded by CYBA, CYBB, NCF1, NCF2 and NCF4 genes. Growing evidence suggests a role of ROS in the modulation of signaling pathways of non-phagocytic cells, including differentiation and proliferation of B-cell progenitors. Transcriptional downregulation of the CYBB gene has been previously reported in cell lines of the B-cell derived classical Hodgkin lymphoma (cHL). Thus, we explored functional consequences of CYBB downregulation on the NADPH complex. Using flow cytometry to detect and quantify superoxide anion synthesis in cHL cell lines we identified recurrent loss of superoxide anion production in all stimulated cHL cell lines in contrast to stimulated non-Hodgkin lymphoma cell lines. As CYBB loss proved to exert a deleterious effect on the NADPH oxidase complex in cHL cell lines, we analyzed the CYBB locus in Hodgkin and Reed-Sternberg (HRS) cells of primary cHL biopsies by in situ hybridisation and identified recurrent deletions of the gene in 8/18 cases. Immunohistochemical analysis to 14 of these cases revealed a complete lack of detectable CYBB protein expression in all HRS cells in all cases studied. Moreover, by microarray profiling of cHL cell lines we identified additional alterations of NADPH oxidase genes including CYBA copy number loss in 3/7 cell lines and a significant downregulation of the NCF1 transcription (p=0.006) compared to normal B-cell subsets. Besides, NCF1 protein was significantly downregulated (p<0.005) in cHL compared to other lymphoma cell lines. Together this findings show recurrent alterations of the NADPH oxidase encoding genes that result in functional inactivation of the enzyme and reduced production of superoxide anion in cHL. © 2013 Giefing et al.

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