scholarly journals Whole-genome Sequencing of Angioimmunoblastic T-Cell Lymphoma Combined With Plasma Cell Leukemia: A Case Report and Review of the Literature

2021 ◽  
Author(s):  
Yang Yang ◽  
Enfan Zhang ◽  
Zhen Cai ◽  
Jingsong He
Keyword(s):  
T Cell ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Cell Lymphoma ◽  
Whole Genome ◽  
Review Of The Literature ◽  
Cell Leukemia ◽  
Angioimmunoblastic T Cell Lymphoma

Abstract Purpose Angioimmunoblastic T-cell lymphoma (AITL) is a distinct subtype of peripheral T-cell lymphomas, sometimes involves proliferation of plasma cells. Currently, only 7 cases of AITL with monoclonal plasmacytosis have been reported. However, the molecular mechanisms underlying the interaction between monoclonal plasma cells and T cells have not been identified. We describe a rare case of AITL with plasma cell leukemia (PCL) in this report. Methods The patient was a 67-year-old female diagnosed with AITL and PCL. CD138 positive plasma cells and CD138-negative mixed bone marrow populations of this patient were collected for whole-genome sequencing (WGS). A review of the literature on AITL cases with monoclonal plasma cells is presented.Results WGS showed that the two cell populatoins shared 282 non-synonymous single nucleotide variants (SNVs) and excess of G to A and C to T transitions. We identified 14 potential driver genes in this patient. Functional enriched analysis of mutant genes confirmed several significantly enriched pathways, including VEGF signaling. The patient was treated with one cycle of PD (combined Bortezomib and Dexamethasone) and Chidamide. However, the patient developed severe pneumonia and pancytopenia, refused to receive further treatment, and died one week after discharge. Conclusion Being aware of the coexistence of PCL and AITL is important for accurate diagnosis and appropriate treatment. In addition, our results suggested the involvement of a group of genes and pathways in AITL with coexisting PCL, providing valuable information for further exploration of the underlying molecular mechanisms.

scholarly journals Clinical Research and Genomic Analysis on Relapsed or Refractory Angioimmunoblastic T Cell Lymphoma with Chidamide Monotherapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5287-5287
Author(s):  
Yu Wu ◽  
Juan Xu ◽  
Yuan Tang ◽  
Yongqian Jia
Keyword(s):  
T Cell ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cell Lymphoma ◽  
Standard Dose ◽  
T Cell Lymphoma ◽  
Sustained Remission ◽  
Whole Genome ◽  
Angioimmunoblastic T Cell Lymphoma ◽  
Tumor Tissues

Abstract BACKGROUND: This study was to evaluate the efficacy and safety of chidamide monotherapy, which is a new histone deacetylase inhibitor (HDAci) of the benzamide class, in relapsed or refractory Angioimmunoblastic T cell lymphoma (AITL), to investigate its genomic expression signatures as well as the mechanisms of chidamide's anti-lymphoma effect and its resistance. METHODS: Two cases with relapsed or refractory AITL were treated with chidamide. We performed a repeated biopsy on relapsed lymphomas and did whole genome next-generation sequencing (NGS) testing on drug -resistant tumor samples. RESULTS: The first patient is a 54-year-old man presented with stage Ⅳ AITL. He underwent autologous stem cell transplantation in his first complete remission (CR) but relapsed 7 months later. In view of resistance to multiple lines of chemotherapy and poor performance status, chidamide was adaministered orally at a standard dose of 30mg twice a week. Pulmonary lesions regressed quickly and a second CR was achieved. Adverse events included grade 2 cytopenias, diarrhea, and reversible QT interval prolongation. The disease free survival was 6 months and AITL relapsed again 4 months ago. He responded to low-dose chidamide combined with lenalidomide and dexamethasone and remains well. Formalin-fixed, paraffin-embeded tumor tissues collected at first relapse were tackled for whole-genome sequencing. The other patient is a 62-year-old woman who had stage Ⅲ AITL. Disease progressed after two cycles of combined chemotherapy, thereafter a standard dose of chidamide monotherapy was initiated. With well tolerability, an unconfirmed CR was achieved and lasted for nearly 3 months. She is still alive but remains refractory to various salvage therapeutics, including chemotherapies, arsenic trioxide, thalidomide, and pralatrexate. A rebiopsy was perferomed and the histopathological findings confirmed the relapse of AITL, associated with Epstein-barr virus infection. Fresh tumor tissues were sent for whole-genome sequencing. In both cases, NGS testing identified mutations of RHOA gene, epigenetic regulators TET2, IDH1, and DNMT3A, as well as CD28. CONCLUSIONS: Chidamide, a low nanomolar inhibitor of HDAC1, 2, 3, and 10, was approved in China for the management of relapsed and/or refractory peripheral T cell lymphoma. It's reported that patients with AITL tended to have higher response rates and more durable responses to chidamide treatment. Our report showed single-agent chidamide is a reasonable approach to treat the formidable disease but seemed difficult to achieve a sustained remission. Various genetic, epigenetic, and immune alterations involve in the pathogensis of AITL, which provide targets for chidamide therapy. High-throughput sequencing approach is very helpful to clarify the mechanisms. Disclosures No relevant conflicts of interest to declare.

Whole Genome and Exome Sequencing Defines The Genetic Landscape Of Hepatosplenic T-Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 842-842
Author(s):  
Paula Scotland ◽  
Philippe Gaulard ◽  
Cassandra L Love ◽  
Virginie Fataccioli ◽  
Marion Travert ◽  
...  
Keyword(s):  
T Cell ◽  
Whole Genome Sequencing ◽  
Exome Sequencing ◽  
Genome Sequencing ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Chromosome 7 ◽  
Whole Genome ◽  
Hepatosplenic T Cell Lymphoma ◽  
Isochromosome 7Q

Abstract Background Hepatosplenic T-cell lymphoma (HSTL) is a rare form of lymphoma, comprising less than 1% of the cases. However, HSTL extracts a highly disproportionate toll on patients with a median age of diagnosis of 35 years and an expected median survival of less than two years. The vast majority of HSTL patients eventually succumb to their disease. The genetic basis of the disease is largely unknown. Although abnormalities of chromosome 7, including isochromosome 7q occur commonly in the disease, the role of specific genes and genetic mutations to the disease remains essentially unknown. Methods In this study, we sought to define the genetic features of HSTL through the whole genome sequencing and exome sequencing of 32 HSTL tumors and germline DNA (where available) from the same patients. Exome enrichment of DNA was carried out using the Agilent solution-based system of exon capture, which uses RNA baits to target all protein coding genes as well as ∼700 human microRNAs. Both whole genome and exome sequencing were performed using the Illumina platform. Results We identified 28 candidate cancer genes that were recurrently mutated in HSTL. Commonly implicated biological processes comprising these genes included signal transduction (e.g. PIK3CD, KRAS) and chromatin modification (e.g. TET1, SETD2 and MLL3), accounting for 16% and 23% of the total genetic events, respectively. Nearly all of these genes have been implicated in HSTL for the first time and provide new insights into the pathogenesis of the disease and potential targets for therapy. Whole genome sequencing confirmed isochromosome 7q as the most common recurrent chromosomal abnormality in HSTL and additional structural genetic alterations in chromosome 7. Conclusion Our study provides the most comprehensive genetic portrait of HSTL to date, and is a significant step in defining the genetic causes of this disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Whole-genome sequencing identifies responders to Pembrolizumab in relapse/refractory natural-killer/T cell lymphoma

Leukemia ◽  
2020 ◽  
Vol 34 (12) ◽  
pp. 3413-3419 ◽  
Author(s):  
Jing Quan Lim ◽  
Dachuan Huang ◽  
Tiffany Tang ◽  
Daryl Tan ◽  
Yurike Laurensia ◽  
...  
Keyword(s):  
T Cell ◽  
Whole Genome Sequencing ◽  
Natural Killer ◽  
Genome Sequencing ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Whole Genome ◽  
Natural Killer T Cell ◽  
Killer T Cell ◽  
Natural Killer T

scholarly journals A case of CD10-negative angioimmunoblastic T cell lymphoma with leukemic change and increased plasma cells mimicking plasma cell leukemia: A case report

2015 ◽  
Vol 10 (3) ◽  
pp. 1555-1560 ◽  
Author(s):  
YASUSHI ADACHI ◽  
TAKUYA HINO ◽  
MASAHIKO OHSAWA ◽  
KAZUHITO UEKI ◽  
TOMOKO MURAO ◽  
...  
Keyword(s):  
Case Report ◽  
T Cell ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Plasma Cell Leukemia ◽  
Cell Leukemia ◽  
Angioimmunoblastic T Cell Lymphoma

TET2 Mutations Revealed by Whole Genome Sequencing in Adult T-Cell Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2697-2697
Author(s):  
Yasunobu Nagata ◽  
Aiko Sato ◽  
Ayana Kon ◽  
Yusuke Okuno ◽  
Kenichi Chiba ◽  
...  
Keyword(s):  
T Cell ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Myeloid Malignancies ◽  
Adult T Cell Leukemia ◽  
T Cell Lymphomas

Abstract Abstract 2697 Adult T cell leukemia (ATL) is an aggressive peripheral T-cell neoplasm highly resistant to conventional therapies. The development of ATL is thought to be initiated by immortalization of T cells by human T cell leukemia virus type I (HTLV-I) infection in early childhood, followed by accumulating genetic hits during a long latency period, which eventually cause neoplastic transformation of T-cells. However, little has been known about those genetic hits that are involved in the pathogenesis of ATL, except for the role of tax protein in T-cell immortalization and alterations of other genes, including TP53, p16 and TCF8. So, in order to understand the genetic basis of ATL, we performed whole genome sequencing of paired-normal DNA from an ATL patient. In total 77 non-silent somatic mutations were detected, among which a TET2 mutation (R1261C) immediately drew our attention. TET2 mutations are found in a wide variety of myeloid malignancies in high frequency and implicated in their pathogenesis. The TET families of proteins are thought to be involved in the epigenetic regulation of gene expression through catalyzing conversion of 5'-methyl cytosine to 5'-hydroxymethyl cytosine, which are supposed to be further converted to unmethylated cytosine. One of the recent interests in TET2 mutations was the recent report of frequent TET2 mutations in peripheral T cell neoplasms, including angioimmunoblastic T-cell lymphomas, peripheral T-cell lymphomas not otherwise specified, as well as other B cell neoplasms, which is in agreement with the observation in TET2-deficient mice, which showed an expansion of bone marrow progenitor pools involving immature lymphoid populations, indicating that deregulated epigenetic machineries could be also involved in the development of mature lymphoid neoplasms. To explore this hypothesis, 144 samples of ATL were screened for mutations in TET2 and other epigenetic regulators commonly mutated in myeloid malignancies, including DNMT3A, IDH1/2 and spliceosome genes, using target deep sequencing. We found 16 TET2 mutations in 13 out of the 144 ATL cases (9%) together with other mutations, which was similar to the frequencies reported in other peripheral T cell neoplasms. Deep sequencing allowed for accurate estimation of allelic burden of these mutations. In most cases, TET2 mutations were found in the major tumor populations, indicating their early origin during clonal evolution. In addition, DNMT3A (2%), IDH1/2 (1%), SF3B1 (2%), ZRSR2 (1%) were also mutated, although at lower frequencies. In conclusion, we found TET2 mutation through whole genome sequencing. TET2 mutations were relatively common in ATL. Together with other mutations frequently found in myeloid malignancies, our finding provided an intriguing insight into the role of deregulated DNA methylation in the pathogenesis of ATL and also suggested that a common mechanism may underlie between the two very different blood cancers. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Whole-genome sequencing reveals potent therapeutic strategy for monomorphic epitheliotropic intestinal T-cell lymphoma

2020 ◽  
Vol 4 (19) ◽  
pp. 4769-4774
Author(s):  
Dachuan Huang ◽  
Jing Quan Lim ◽  
Daryl Ming Zhe Cheah ◽  
Khalilatul Hanisah Binte Mohd Kahliab ◽  
Yurike Laurensia ◽  
...  
Keyword(s):  
T Cell ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Therapeutic Strategy ◽  
Cell Lymphoma ◽  
Synergistic Effects ◽  
T Cell Lymphoma ◽  
Whole Genome ◽  
Pdx Model ◽  
Key Points

Key Points Whole genomic and transcriptomic analyses of MEITL revealed multiple potential therapeutic targets. Synergistic effects of pimozide and romidepsin are shown in a well-characterized MEITL PDX model.

scholarly journals Experimental evolution of gallium resistance in Escherichia coli

2019 ◽  
Vol 2019 (1) ◽  
pp. 169-180
Author(s):  
Joseph L Graves ◽  
Akamu J Ewunkem ◽  
Jason Ward ◽  
Constance Staley ◽  
Misty D Thomas ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Experimental Evolution ◽  
Molecular Mechanisms ◽  
Gallium Nitrate ◽  
Whole Genome ◽  
Mechanisms Of Resistance ◽  
Genomic Changes ◽  
K 12

Abstract Background and Objectives Metallic antimicrobial materials are of growing interest due to their potential to control pathogenic and multidrug-resistant bacteria. Yet we do not know if utilizing these materials can lead to genetic adaptations that produce even more dangerous bacterial varieties. Methodology Here we utilize experimental evolution to produce strains of Escherichia coli K-12 MG1655 resistant to, the iron analog, gallium nitrate (Ga(NO3)3). Whole genome sequencing was utilized to determine genomic changes associated with gallium resistance. Computational modeling was utilized to propose potential molecular mechanisms of resistance. Results By day 10 of evolution, increased gallium resistance was evident in populations cultured in medium containing a sublethal concentration of gallium. Furthermore, these populations showed increased resistance to ionic silver and iron (III), but not iron (II) and no increase in traditional antibiotic resistance compared with controls and the ancestral strain. In contrast, the control populations showed increased resistance to rifampicin relative to the gallium-resistant and ancestral population. Genomic analysis identified hard selective sweeps of mutations in several genes in the gallium (III)-resistant lines including: fecA (iron citrate outer membrane transporter), insl1 (IS30 tranposase) one intergenic mutations arsC →/→ yhiS; (arsenate reductase/pseudogene) and in one pseudogene yedN ←; (iapH/yopM family). Two additional significant intergenic polymorphisms were found at frequencies > 0.500 in fepD ←/→ entS (iron-enterobactin transporter subunit/enterobactin exporter, iron-regulated) and yfgF ←/→ yfgG (cyclic-di-GMP phosphodiesterase, anaerobic/uncharacterized protein). The control populations displayed mutations in the rpoB gene, a gene associated with rifampicin resistance. Conclusions This study corroborates recent results observed in experiments utilizing pathogenic Pseudomonas strains that also showed that Gram-negative bacteria can rapidly evolve resistance to an atom that mimics an essential micronutrient and shows the pleiotropic consequences associated with this adaptation. Lay summary We utilize experimental evolution to produce strains of Escherichia coli K-12 MG1655 resistant to, the iron analog, gallium nitrate (Ga(NO3)3). Whole genome sequencing was utilized to determine genomic changes associated with gallium resistance. Computational modeling was utilized to propose potential molecular mechanisms of resistance.

scholarly journals Whole genome sequencing analysis of high confidence variants of B-cell lymphoma in Canis familiaris

PLoS ONE ◽  
2020 ◽  
Vol 15 (8) ◽  
pp. e0238183
Author(s):  
Alana Sparks ◽  
J. Paul Woods ◽  
Dorothee Bienzle ◽  
Geoffrey A. Wood ◽  
Brenda Lynn Coomber
Keyword(s):  
B Cell ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cell Lymphoma ◽  
Canis Familiaris ◽  
B Cell Lymphoma ◽  
Whole Genome ◽  
Sequencing Analysis ◽  
High Confidence
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