primary effusion lymphoma
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Biology ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 132
Author(s):  
Roberta Gonnella ◽  
Luisa Guttieri ◽  
Maria Saveria Gilardini Montani ◽  
Roberta Santarelli ◽  
Erica Bassetti ◽  
...  

We have previously shown that Zinc supplementation triggered ER stress/UPR in cancer cells undergoing treatment by genotoxic agents, reactivated wtp53 in cancer cells harboring mutant p53 (mutp53) and potentiated the activity of wtp53 in those carrying wtp53. In this study, we used Zinc chloride alone or in combination with 2 Gy radiation to treat Primary Effusion Lymphoma (PEL) cells, an aggressive B-cell lymphoma associated with KSHV that harbors wt or partially functioning p53. We found that Zinc triggered a mild ER stress/UPR in these lymphoma cells and activated ERK1/2, molecule known to sustain cell survival in the course of UPR activation. In combination with radiations, Zinc triggered a stronger p53 activation that counteracted its mediated ERK1/2 phosphorylation, further upregulating the UPR molecule CHOP and promoting cell death. These data suggest that Zinc supplementation could be a promising strategy to reduce the doses of radiation and possibly of other DNA-damaging agents to obtain an efficient capacity to induce lymphoma cell death.


2021 ◽  
Vol 19 (4) ◽  
pp. e47
Author(s):  
Anisur Rahman ◽  
Shipan Das Gupta ◽  
Md. Anisur Rahman ◽  
Saheda Tamanna

Kaposi's sarcoma-associated herpesvirus (KSHV) is one of the few human oncogenic viruses, which causes a variety of malignancies, including Kaposi's sarcoma, multicentric Castleman disease, and primary effusion lymphoma, particularly in human immunodeficiency virus patients. The currently available treatment options cannot always prevent the invasion and dissemination of this virus. In recent times, siRNA-based therapeutics are gaining prominence over conventional medications as siRNA can be designed to target almost any gene of interest. The ORF57 is a crucial regulatory protein for lytic gene expression of KSHV. Disruption of this gene translation will inevitably inhibit the replication of the virus in the host cell. Therefore, the ORF57 of KSHV could be a potential target for designing siRNA-based therapeutics. Considering both sequence preferences and target site accessibility, several online tools (i-SCORE Designer, Sfold web server) had been utilized to predict the siRNA guide strand against the ORF57. Subsequently, off-target filtration (BLAST), conservancy test (fuzznuc), and thermodynamics analysis (RNAcofold, RNAalifold, and RNA Structure web server) were also performed to select the most suitable siRNA sequences. Finally, two siRNAs were identified that passed all of the filtration phases and fulfilled the thermodynamic criteria. We hope that the siRNAs predicted in this study would be helpful for the development of new effective therapeutics against KSHV.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Michiko Shimoda ◽  
Yuanzhi Lyu ◽  
Kang-Hsin Wang ◽  
Ashish Kumar ◽  
Hiroki Miura ◽  
...  

AbstractIn herpesvirus replicating cells, host cell gene transcription is frequently down-regulated because important transcriptional apparatuses are appropriated by viral transcription factors. Here, we show a small peptide derived from the Kaposi’s sarcoma-associated herpesvirus transactivator (K-Rta) sequence, which attenuates cellular MYC expression, reduces cell proliferation, and selectively kills cancer cell lines in both tissue culture and a xenograft tumor mouse model. Mechanistically, the peptide functions as a decoy to block the recruitment of coactivator complexes consisting of Nuclear receptor coactivator 2 (NCOA2), p300, and SWI/SNF proteins to the MYC promoter in primary effusion lymphoma cells. Thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM seq) with target-transcriptional analyses further confirm that the viral peptide directly attenuates MYC and MYC-target gene expression. This study thus provides a unique tool to control MYC activation, which may be used as a therapeutic payload to treat MYC-dependent diseases such as cancers and autoimmune diseases.


Hemato ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 703-712
Author(s):  
Mark Bower ◽  
Antonino Carbone

In 1992, Kaposi sarcoma herpesvirus (KSHV/HHV8) was discovered and identified as the causative agent for Kaposi sarcoma. Subsequently, the presence of this virus has been detected in a number of lymphoproliferative disorders in people living with HIV (PLWH), including: KSHV-associated multicentric Castleman disease, primary effusion lymphoma, KSHV-positive diffuse large B-cell lymphoma, and germinotropic lymphoproliferative disorder. Each of these rare entities has subsequently been diagnosed in HIV-negative individuals. The recognition of some of these KSHV/HHV8-associated lymphoproliferative disorders has led to their inclusion in the WHO classification of lymphomas in 2008 and the revision of 2016; however, further revision is under way to update the classification. The relatively recent recognition of these lymphoproliferative disorders and their low incidence, particularly in the HIV-negative population, means that there is little published evidence and consensus on their clinical features and management. The publication of a new WHO classification of lymphomas should yield diagnostic clarity, providing an impetus for retrospective case series and prospective clinical trials in these KSHV/HHV8-associated lymphoproliferative disorders.


2021 ◽  
Author(s):  
Gunya Sittithumcharee ◽  
Ryusho Kariya ◽  
Teerapich Kasemsuk ◽  
Rungnapha Saeeng ◽  
Seiji Okada

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1188-1188
Author(s):  
Jouliana Sadek ◽  
Jan Krumsiek ◽  
Tuo Zhang ◽  
Barbara Coan ◽  
Maite Ibañez de Garayo ◽  
...  

Abstract Although nucleoside analogues have been used effectively in the clinic for the treatment of a wide range of hematological malignancies, lack of response to currently available nucleoside analogues and drug resistance limit their utility. A rare but highly aggressive cancer is primary effusion lymphoma (PEL). Through high throughput screening, we have discovered a novel nucleoside analog, called 6-ethylthioinosine (6-ETI) as a potent and selective inhibitor of PEL, with little activity in other lymphomas tested. PEL is a rare B-cell non-Hodgkin's lymphoma characterized by lymphomatous effusions in body cavities. It is associated with Kaposi's sarcoma herpesvirus (KSHV/HHV-8) infection and occurs mainly in immunocompromised patients. PEL is known to frequently be resistant to conventional chemotherapy (CHOP and EPOCH) resulting in poor prognosis and a rather incurable disease. Our studies demonstrated that 6-ETI is a pro-drug activated by adenosine kinase (ADK), an enzyme that is overexpressed in PEL cell lines and primary PEL specimens, as well as other plasma cell malignancies, including plasmablastic lymphoma (PBL) and multiple myeloma (MM). The latter is also responsive to 6-ETI in vitro and in mouse models. 6-ETI induces S phase arrest and inhibits DNA synthesis. RNA sequencing of in vitro generated PEL resistant clones and CRISPR knock out of ADK (ADK KO), respectively, indicated that mutations or loss of expression of ADK renders cells resistant to treatment. This data demonstrates that ADK expression can be used as a predictive biomarker of response to 6-ETI, which can help identify which patients are more likely to respond to this treatment. We investigated which pathways are differentially regulated in sensitive and resistant cells to better delineate the mechanism of action of 6-ETI and to design effective combinatorial regimens and prevent resistance. We found that drug sensitivity was associated with AMPK activation and inhibition of PI3K/mTOR/p70S6K signaling. Little is known about the function of ADK in plasma cell neoplasms. Knock-out of this protein in PEL, or use of ADK chemical inhibitors, do not affect their viability. Thus, we used ADK KO cell lines to examine the role of ADK in these tumors and to determine if cells undergo adaptations that may contribute to 6-ETI resistance and represent potential vulnerabilities to combat it. We performed metabolic and transcriptomic profiling of wild type (WT) (6-ETI sensitive) and ADK KO (6-ETI resistant) cells to achieve a comprehensive assessment of all the metabolic perturbations and gene expression changes induced by knocking out ADK. We also treated these cells with 6-ETI to examine the effects in sensitive and resistant cells. This integrated analysis revealed that 6-ETI depletes sensitive PEL cells of their nucleotide pools accompanied by the downregulation of several genes in purine and pyrimidine biosynthesis pathways. We found that adenine supplementation rescues sensitive PEL cells from 6-ETI induced cytotoxicity, reverses p70S6K inhibition and restores DNA synthesis suggesting that purine metabolism is a critical mediator of 6-ETI induced cytotoxicity. Using seahorse bioenergetic assay, we show that ADK KO resistant cells have impaired mitochondrial respiration indicating that ADK plays a critical role in mitochondrial bioenergetics. Metabolic profiling of these ADK KO resistant cells showed that these cells have elevated levels of de novo pyrimidine metabolic intermediates. Metabolic flux through de novo pyrimidine is controlled by the rate limiting enzyme CAD. The activity of CAD is regulated by ribosomal protein S6 Kinase 1(S6K1) by phosphorylation at its (Ser1859) site. Using western blotting, we observed a striking increase of phosphorylation of CAD at its S6K1 site (Ser1859) in ADK KO cells compared to WT cells. This is the first to date study that characterizes the role of ADK in lymphomas. Our data indicates that ADK KO cells have undergone metabolic reprogramming to upregulate de novo pyrimidine biosynthesis and p70S6K signaling. Moreover, we found that 6-ETI synergizes with the pan PI3K inhibitor BKM120 highlighting nucleotide metabolism and PI3K/mTOR signaling as key therapeutic vulnerabilities targeted by this novel nucleoside analog. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2503-2503
Author(s):  
Jennifer Morgan ◽  
Jennifer S Smith ◽  
Chandrika Rao ◽  
Dominic T. Moore ◽  
Christopher Dittus

Abstract Background: Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in the United States. NHL comprises a heterogeneous group of over 40 histological subtypes, each of which has distinct genetic, morphologic and clinical features. While NHL epidemiology as a single entity has been well-characterized using population-based cancer registry data, the epidemiology of NHL subtypes is not well understood and even less data are available for rarer subtypes. We aimed to determine geodemographic correlates for NHL subtypes in North Carolina to provide rarely reported epidemiologic characterization of each distinct malignancy. Methods: Demographic data were obtained on all NHL subtypes reported in persons >18 years of age from 2009-2019 from the North Carolina Central Cancer Registry (NCCCR). NHL subtypes were determined based on World Health Organization International Classification of Diseases for Oncology,Third Edition (ICD-O-3) Morphology codes provided by NCCCR. Crude incidence and mortality rates were estimated per 100,000 persons for the 10-year period using 2019 population data from the U.S Census Bureau. Urban and rural residence designations were based on zip code using rural-urban commuting codes developed by the Rural Health Research Center. County tier designations were used as markers of economic prosperity, with 3 being most prosperous, and provided by the North Carolina Department of Commerce. Data are being mapped using ESRI ArcMap 10.8.1. Results: A total of 25,627 incident cases of NHL and 9,930 associated deaths were reported between 2009 and 2019 in North Carolina. Therefore, the standard NHL incidence and mortality rates are 24.1 and 9.3 per 100,000 persons. For incident NHL cases, median age at diagnosis was 68 years (range 19-103), 55% were male and 45% female. Most (83%) identified as white, 14% as black, and 3% as other. Median age at death was 70 years (range 19-106). Twenty-eight NHL subtypes were identified with the four most common NHL subtypes being Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Diffuse Large B Cell Lymphoma (DLBCL), Follicular Lymphoma (FL), and Marginal Zone Lymphoma with 6.54, 6.42, 3.55, and 2.0 cases (per 100,000 persons), respectively. Least common subtypes included Intravascular Large B Cell Lymphoma, Primary Effusion Lymphoma, Primary Cutaneous Gamma Delta T-cell Lymphoma (PCGD-TCL) and Subcutaneous Panniculitis-Like T-cell Lymphoma, all with 0.01 cases per 100,000 persons (or 15, 14, 9 and 6 cases respectively). The distribution of NHL subtypes varied according to demographics with several notable findings. DLBCL had the highest crude mortality rate of 2.98 deaths/100,000 persons, followed by CLL (2.12 deaths/100,000 persons), FL (0.98 deaths/100,000 persons) and Lymphoma NOS (0.51 deaths/100,00 persons). Mediastinal Large B-cell Lymphoma (MLBCL) was diagnosed in the youngest individuals with median age of 36 (range 20-74), whereas PCGD-TCL occurred in the oldest with median age of 74 (range 31-99). Primary Effusion Lymphoma had the highest male predominance (93%) and MLBCL had the highest female predominance (73%). Mantle Cell Lymphoma had the highest predominance of persons who identify as white (90%), Anaplastic Large Cell Lymphoma (ALK+/-) with those who identify as black (66%), and Primary Effusion Lymphoma with those who identify as other (14%). Predominance of rurality and county tier designations varied by NHL subtype. Conclusions: A registry-based assessment of NHL subtypes illustrates the heterogeneous nature of this group of malignancies and highlights significant variation in the geodemographic features of each subtype. Evaluating geodemographic correlates deepens our understanding of NHL subtypes and can inform populations at risk for each unique NHL subtype. Figure 1 Figure 1. Disclosures Dittus: BeiGene: Other: Advisory Board; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding.


2021 ◽  
Vol 8 (11) ◽  
pp. e00698
Author(s):  
Sarah Mushtaq ◽  
Sabrina Prabakaran ◽  
Maher Elharake ◽  
Sayeef Mirza ◽  
Adharsh Ravindran ◽  
...  

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