RESUMEN
Burkitt lymphoma is a non-Hodgkin B-cell lymphoma with a high prevalence in the pediatric population. Abdominal manifestations are well known in sporadic Burkitt lymphoma and vary from nonspecific symptoms to intestinal obstruction due to intussusception; however, mass-like splenic involvement has been scarcely described. OBJECTIVE: To present a case of a patient with a splenic mass whose histopathological analysis revealed Burkitt lymphoma. CLINICAL CASE: A 13-year-old female patient presented with abdominal pain, progressive weight loss, and fever. Imaging studies showed a splenic mass, intestinal thickening, and ileal intussusception. Histopathological analysis of spleen biopsy revealed Burkitt lymphoma. After the first cycle of chemotherapy (BFM95-NHL protocol), abdominal symptoms resolved; no other signs suggestive of intussusception were observed, as well as a significant reduction of the splenic mass was observed. CONCLUSIONS: Burkitt lymphoma in pediatric patients can present as a well-defined splenic tumor, causing no splenomegaly. In addition, its management does not require surgery since it can be resolved with chemotherapy.
Asunto(s)
Linfoma de Burkitt , Neoplasias del Bazo , Humanos , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/patología , Linfoma de Burkitt/complicaciones , Linfoma de Burkitt/tratamiento farmacológico , Femenino , Adolescente , Neoplasias del Bazo/patología , Neoplasias del Bazo/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Intususcepción/diagnóstico , Intususcepción/etiología , Dolor Abdominal/etiologíaAsunto(s)
Linfoma de Burkitt , Herpesvirus Humano 4 , Factores de Transcripción SOXC , Adulto , Femenino , Humanos , Masculino , Linfoma de Burkitt/patología , Linfoma de Burkitt/genética , Linfoma de Burkitt/virología , Linfoma de Burkitt/diagnóstico , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/patología , Herpesvirus Humano 4/aislamiento & purificación , Factores de Transcripción SOXC/genética , Factores de Transcripción SOXC/metabolismoAsunto(s)
Mutación , Humanos , Linfoma de Burkitt/genética , Linfoma de Burkitt/patología , Masculino , Infecciones por Virus de Epstein-Barr/genética , Proteínas Tirosina Quinasas/genética , Linfadenopatía/genética , Linfadenopatía/patología , Síndromes de Inmunodeficiencia/genética , Síndrome Linfoproliferativo Autoinmune/genética , Síndrome Linfoproliferativo Autoinmune/diagnóstico , Femenino , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/patología , Enfermedades de Inmunodeficiencia Primaria/genéticaRESUMEN
Most mature B-cell malignancies originate from the malignant transformation of germinal center (GC) B cells. The GC reaction appears to have a role in malignant transformation, in which a major player of the GC reaction is BCL6, a key regulator of this process. We now demonstrate that BCL6 protein levels were dramatically decreased in Epstein-Barr virus (EBV)-positive lymphoblastoid cell lines and Burkitt's lymphoma cell lines. Notably, BCL6 degradation was significantly enhanced in the presence of both EBNA3C and FBXO11. Furthermore, the amino-terminal domain of EBNA3C, which contains residues 50-100, interacts directly with FBXO11. The expression of EBNA3C and FBXO11 resulted in a significant induction of cell proliferation. Furthermore, BCL6 protein expression levels were regulated by EBNA3C via the Skp Cullin Fbox (SCF)FBXO11 complex, which mediated its ubiquitylation, and knockdown of FBXO11 suppressed the transformation of lymphoblastoid cell lines. These data provide new insights into the function of EBNA3C in B-cell transformation during GC reaction and raise the possibility of developing new targeted therapies against EBV-associated cancers. IMPORTANCE: The novel revelation in our study involves the suppression of BCL6 expression by the essential Epstein-Barr virus (EBV) antigen EBNA3C, shedding new light on our current comprehension of how EBV contributes to lymphomagenesis by impeding the germinal center reaction. It is crucial to note that while several EBV latent proteins are expressed in infected cells, the collaborative mechanisms among these proteins in regulating B-cell development or inducing B-cell lymphoma require additional investigation. Nonetheless, our findings carry significance for the development of emerging strategies aimed at addressing EBV-associated cancers.
Asunto(s)
Antígenos Nucleares del Virus de Epstein-Barr , Proteínas F-Box , Herpesvirus Humano 4 , Proteínas Proto-Oncogénicas c-bcl-6 , Humanos , Antígenos Nucleares del Virus de Epstein-Barr/metabolismo , Antígenos Nucleares del Virus de Epstein-Barr/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas F-Box/metabolismo , Proteínas F-Box/genética , Herpesvirus Humano 4/metabolismo , Herpesvirus Humano 4/genética , Línea Celular Tumoral , Linfocitos B/metabolismo , Linfocitos B/virología , Infecciones por Virus de Epstein-Barr/metabolismo , Infecciones por Virus de Epstein-Barr/virología , Proteolisis , Proliferación Celular , Ubiquitinación , Linfoma de Burkitt/virología , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/genética , Linfoma de Burkitt/patología , Antígenos Virales/metabolismo , Antígenos Virales/genética , Centro Germinal/metabolismo , Centro Germinal/virología , Proteína-Arginina N-MetiltransferasasRESUMEN
Burkitt's lymphoma (BL) is a rare and highly aggressive B-cell non-Hodgkin lymphoma. Although the outcomes of patients with BL have greatly improved, options for patients with relapsed and refractory BL are limited. Therefore, there is an urgent need to improve BL therapeutics and to develop novel drugs with reduced toxicity. In this study, we demonstrated that enolase 1 (ENO1) is a potential novel drug target for BL treatment. We determined that ENO1 was aberrantly upregulated in BL, which was closely related to its invasiveness and poor clinical outcomes. Furthermore, using RNA interference, we demonstrated that ENO1 depletion significantly inhibited cell proliferation and invasion both in vitro and in vivo. Mechanistically, we established that ENO1 knockdown suppressed the PI3K-AKT and epithelial-mesenchymal transition (EMT) signaling pathways by reducing plasminogen (PLG) recruitment, plasmin (PL) generation, and TGF-ß1 activation. Addition of activated TGF-ß1 protein to the culture medium of shENO1 cells reversed the inhibitory effects on cell proliferation and invasion, as well as those on the PI3K-AKT and EMT signaling pathways. Notably, our research led to the discovery of a novel ENO1-PLG interaction inhibitor, Ciwujianoside E (L-06). L-06 effectively disrupts the interaction between ENO1 and PLG, consequently reducing PL generation and suppressing TGF-ß1 activation. In both in vitro and in vivo experiments, L-06 exerted impressive antitumor effects. In summary, our study elucidated the critical role of ENO1 in BL cell proliferation and invasion and introduced a novel ENO1 inhibitor, which holds promise for improving the treatment of patients with BL in the future.
Asunto(s)
Linfoma de Burkitt , Proliferación Celular , Proteínas de Unión al ADN , Transición Epitelial-Mesenquimal , Invasividad Neoplásica , Fosfopiruvato Hidratasa , Plasminógeno , Factor de Crecimiento Transformador beta1 , Proteínas Supresoras de Tumor , Fosfopiruvato Hidratasa/metabolismo , Humanos , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Animales , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/patología , Linfoma de Burkitt/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Plasminógeno/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Masculino , Ratones Desnudos , Femenino , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones , Ratones Endogámicos BALB C , Movimiento Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Biomarcadores de TumorRESUMEN
ABSTRACT: Burkitt lymphoma (BL) is characterized by a tumor microenvironment (TME) in which macrophages represent the main component, determining a distinct histological appearance known as "starry sky" pattern. However, in some instances, BL may exhibit a granulomatous reaction that has been previously linked to favorable prognosis and spontaneous regression. The aim of our study was to deeply characterize the immune landscape of 7 cases of Epstein-Barr virus-positive (EBV+) BL with granulomatous reaction compared with 8 cases of EBV+ BL and 8 EBV-negative (EBV-) BL, both with typical starry sky pattern, by Gene expression profiling performed on the NanoString nCounter platform. Subsequently, the data were validated using multiplex and combined immunostaining. Based on unsupervised clustering of differentially expressed genes, BL samples formed 3 distinct clusters differentially enriched in BL with a diffuse granulomatous reaction (cluster 1), EBV+ BL with typical starry sky pattern (cluster 2), EBV- BL with typical "starry sky" (cluster 3). We observed variations in the immune response signature among BL with granulomatous reaction and BL with typical "starry sky," both EBV+ and EBV-. The TME signature in BL with diffuse granulomatous reaction showed a proinflammatory response, whereas BLs with "starry sky" were characterized by upregulation of M2 polarization and protumor response. Moreover, the analysis of additional signatures revealed an upregulation of the dark zone signature and epigenetic signature in BL with a typical starry sky. Tumor-associated macrophages and epigenetic regulators may be promising targets for additional therapies for BL lymphoma, opening novel immunotherapeutic strategies.
Asunto(s)
Linfoma de Burkitt , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Linfoma de Burkitt/inmunología , Linfoma de Burkitt/patología , Linfoma de Burkitt/genética , Femenino , Masculino , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/inmunología , Perfilación de la Expresión Génica , Herpesvirus Humano 4 , Adulto , Transcriptoma , Persona de Mediana Edad , Regulación Neoplásica de la Expresión Génica , Niño , Adolescente , PronósticoRESUMEN
Glucocorticoids have been used for decades to treat lymphomas without an established mechanism of action. Using functional genomic, proteomic, and chemical screens, we discover that glucocorticoids inhibit oncogenic signaling by the B cell receptor (BCR), a recurrent feature of aggressive B cell malignancies, including diffuse large B cell lymphoma and Burkitt lymphoma. Glucocorticoids induce the glucocorticoid receptor (GR) to directly transactivate genes encoding negative regulators of BCR stability (LAPTM5; KLHL14) and the PI3 kinase pathway (INPP5D; DDIT4). GR directly represses transcription of CSK, a kinase that limits the activity of BCR-proximal Src-family kinases. CSK inhibition attenuates the constitutive BCR signaling of lymphomas by hyperactivating Src-family kinases, triggering their ubiquitination and degradation. With the knowledge that glucocorticoids disable oncogenic BCR signaling, they can now be deployed rationally to treat BCR-dependent aggressive lymphomas and used to construct mechanistically sound combination regimens with inhibitors of BTK, PI3 kinase, BCL2, and CSK.
Asunto(s)
Glucocorticoides , Receptores de Antígenos de Linfocitos B , Humanos , Glucocorticoides/farmacología , Receptores de Antígenos de Linfocitos B/metabolismo , Animales , Transducción de Señal/efectos de los fármacos , Receptores de Glucocorticoides/metabolismo , Ratones , Línea Celular Tumoral , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/genética , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patología , Terapia Molecular Dirigida/métodos , Fosfatidilinositol 3-Quinasas/metabolismo , Familia-src Quinasas/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
Primary gastric Burkitt's lymphoma is an aggressive non-Hodgkin's lymphoma that has been rarely reported in the literature. The majority of primary gastric lymphomas are diffuse large B-cell lymphomas and mucosa-associated lymphoid tissue (MALT) lymphomas. Patients with primary gastric Burkitt's lymphoma can present with abdominal pain, hematemesis, melena, perforation, and obstruction. Diagnosis is made with a combination of clinical, radiological, and pathological findings. Treatment data are limited due to the limited cases reported. We present a case of a 47-year-old female who presented with diffuse abdominal pain, melena, and coffee-ground emesis that was diagnosed with primary gastric Burkitt's lymphoma following biopsies taken from a gastric ulcerated mass found on upper endoscopy.
Asunto(s)
Linfoma de Burkitt , Neoplasias Gástricas , Humanos , Femenino , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/patología , Persona de Mediana Edad , Neoplasias Gástricas/patología , Neoplasias Gástricas/diagnóstico , Dolor Abdominal/etiología , Biopsia , Melena/etiología , Tomografía Computarizada por Rayos X , Linfoma no HodgkinRESUMEN
Although the toxicity of arsenic depends on its chemical forms, few studies have taken into account the ambiguous phenomenon that sodium arsenite (NaAsO2) acts as a potent carcinogen while arsenic trioxide (ATO, As2O3) serves as an effective therapeutic agent in lymphoma, suggesting that NaAsO2 and As2O3 may act via paradoxical ways to either promote or inhibit cancer pathogenesis. Here, we compared the cellular response of the two arsenical compounds, NaAsO2 and As2O3, on the Burkitt lymphoma cell model, the Epstein Barr Virus (EBV)-positive P3HR1 cells. Using flow cytometry and biochemistry analyses, we showed that a NaAsO2 treatment induces P3HR1 cell death, combined with drastic drops in ΔΨm, NAD(P)H and ATP levels. In contrast, As2O3-treated cells resist to cell death, with a moderate reduction of ΔΨm, NAD(P)H and ATP. While both compounds block cells in G2/M and affect their protein carbonylation and lipid peroxidation, As2O3 induces a milder increase in superoxide anions and H2O2 than NaAsO2, associated to a milder inhibition of antioxidant defenses. By electron microscopy, RT-qPCR and image cytometry analyses, we showed that As2O3-treated cells display an overall autophagic response, combined with mitophagy and an unfolded protein response, characteristics that were not observed following a NaAsO2 treatment. As previous works showed that As2O3 reactivates EBV in P3HR1 cells, we treated the EBV- Ramos-1 cells and showed that autophagy was not induced in these EBV- cells upon As2O3 treatment suggesting that the boost of autophagy observed in As2O3-treated P3HR1 cells could be due to the presence of EBV in these cells. Overall, our results suggest that As2O3 is an autophagic inducer which action is enhanced when EBV is present in the cells, in contrast to NaAsO2, which induces cell death. That's why As2O3 is combined with other chemicals, as all-trans retinoic acid, to better target cancer cells in therapeutic treatments.
Asunto(s)
Trióxido de Arsénico , Arsenicales , Arsenitos , Autofagia , Mitocondrias , Estrés Oxidativo , Óxidos , Compuestos de Sodio , Trióxido de Arsénico/farmacología , Arsenitos/farmacología , Arsenitos/toxicidad , Humanos , Estrés Oxidativo/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Compuestos de Sodio/farmacología , Arsenicales/farmacología , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Óxidos/farmacología , Muerte Celular/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Herpesvirus Humano 4/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Peróxido de Hidrógeno/farmacología , Peroxidación de Lípido/efectos de los fármacos , Linfoma de Burkitt/virología , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patología , Linfoma de Burkitt/tratamiento farmacológicoRESUMEN
ABSTRACT: SRY-related HMG-box gene 11 (SOX11) is a transcription factor overexpressed in mantle cell lymphoma (MCL), a subset of Burkitt lymphomas (BL) and precursor lymphoid cell neoplasms but is absent in normal B cells and other B-cell lymphomas. SOX11 has an oncogenic role in MCL but its contribution to BL pathogenesis remains uncertain. Here, we observed that the presence of Epstein-Barr virus (EBV) and SOX11 expression were mutually exclusive in BL. SOX11 expression in EBV-negative (EVB-) BL was associated with an IGâ·MYC translocation generated by aberrant class switch recombination, whereas in EBV-negative (EBV-)/SOX11-negative (SOX11-) tumors the IGâ·MYC translocation was mediated by mistaken somatic hypermutations. Interestingly, EBV- SOX11-expressing BL showed higher frequency of SMARCA4 and ID3 mutations than EBV-/SOX11- cases. By RNA sequencing, we identified a SOX11-associated gene expression profile, with functional annotations showing partial overlap with the SOX11 transcriptional program of MCL. Contrary to MCL, no differences on cell migration or B-cell receptor signaling were found between SOX11- and SOX11-positive (SOX11+) BL cells. However, SOX11+ BL showed higher adhesion to vascular cell adhesion molecule 1 (VCAM-1) than SOX11- BL cell lines. Here, we demonstrate that EBV- BL comprises 2 subsets of cases based on SOX11 expression. The mutual exclusion of SOX11 and EBV, and the association of SOX11 with a specific genetic landscape suggest a role of SOX11 in the early pathogenesis of BL.
Asunto(s)
Linfoma de Burkitt , Herpesvirus Humano 4 , Factores de Transcripción SOXC , Humanos , Linfoma de Burkitt/genética , Linfoma de Burkitt/virología , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patología , Factores de Transcripción SOXC/genética , Factores de Transcripción SOXC/metabolismo , Herpesvirus Humano 4/genética , Regulación Neoplásica de la Expresión Génica , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/virología , Mutación , ADN Helicasas/genética , ADN Helicasas/metabolismo , Translocación Genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Masculino , Proteínas Inhibidoras de la Diferenciación/genética , Proteínas Inhibidoras de la Diferenciación/metabolismo , Proteínas NuclearesRESUMEN
MYC-rearranged B-cell lymphoma (BCL) in the pediatric/young adult (YA) age group differs substantially in disease composition from adult cohorts. However, data regarding the partner genes, concurrent rearrangements, and ultimate diagnoses in these patients is scarce compared to that in adult cohorts. We aimed to characterize the spectrum of MYC-rearranged (MYC-R) mature, aggressive BCL in the pediatric/YA population. A retrospective study of morphologic, immunophenotypic, and fluorescence in situ hybridization (FISH) results of patients age ≤ 30 years with suspected Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL), and a MYC-R by FISH between 2013-2022 was performed. Two-hundred fifty-eight cases (129 (50%) pediatric (< 18 years) and 129 (50%) YA (18-30 years)) were included. Most MYC-R BCL in pediatric (89%) and YA (66%) cases were BL. While double-hit (DH) cytogenetics (MYC with BCL2 and/or BCL6-R, HGBCL-DH) was rare in the pediatric population (2/129, 2%), HGBCL-DH increased with age and was identified in 17/129 (13%) of YA cases. Most HGBCL-DH had MYC and BCL6-R, while BCL2-R were rare in both groups (3/258, 1%). MYC-R without an IG partner was more common in the YA group (14/116 (12%) vs 2/128 (2%), p = 0.001). The pediatric to YA transition is characterized by decreasing frequency in BL and increasing genetic heterogeneity of MYC-R BCL, with emergence of DH-BCL with MYC and BCL6-R. FISH to evaluate for BCL2 and BCL6 rearrangements is likely not warranted in the pediatric population but should continue to be applied in YA BCL.
Asunto(s)
Reordenamiento Génico , Proteínas Proto-Oncogénicas c-myc , Humanos , Adolescente , Niño , Masculino , Adulto Joven , Adulto , Femenino , Proteínas Proto-Oncogénicas c-myc/genética , Estudios Retrospectivos , Preescolar , Hibridación Fluorescente in Situ , Linfoma de Células B/genética , Linfoma de Células B/patología , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologíaRESUMEN
Epstein-Barr virus (EBV) is an important cause of human lymphomas, including Burkitt lymphoma (BL). EBV+ BLs are driven by Myc translocation and have stringent forms of viral latency that do not express either of the two major EBV oncoproteins, EBNA2 (which mimics Notch signaling) and LMP1 (which activates NF-κB signaling). Suppression of Myc-induced apoptosis, often through mutation of the TP53 (p53) gene or inhibition of pro-apoptotic BCL2L11 (BIM) gene expression, is required for development of Myc-driven BLs. EBV+ BLs contain fewer cellular mutations in apoptotic pathways compared to EBV-negative BLs, suggesting that latent EBV infection inhibits Myc-induced apoptosis. Here we use an EBNA2-deleted EBV virus (ΔEBNA2 EBV) to create the first in vivo model for EBV+ BL-like lymphomas derived from primary human B cells. We show that cord blood B cells infected with both ΔEBNA2 EBV and a Myc-expressing vector proliferate indefinitely on a CD40L/IL21 expressing feeder layer in vitro and cause rapid onset EBV+ BL-like tumors in NSG mice. These LMP1/EBNA2-negative Myc-driven lymphomas have wild type p53 and very low BIM, and express numerous germinal center B cell proteins (including TCF3, BACH2, Myb, CD10, CCDN3, and GCSAM) in the absence of BCL6 expression. Myc-induced activation of Myb mediates expression of many of these BL-associated proteins. We demonstrate that Myc blocks LMP1 expression both by inhibiting expression of cellular factors (STAT3 and Src) that activate LMP1 transcription and by increasing expression of proteins (DNMT3B and UHRF1) known to enhance DNA methylation of the LMP1 promoters in human BLs. These results show that latent EBV infection collaborates with Myc over-expression to induce BL-like human B-cell lymphomas in mice. As NF-κB signaling retards the growth of EBV-negative BLs, Myc-mediated repression of LMP1 may be essential for latent EBV infection and Myc translocation to collaboratively induce human BLs.
Asunto(s)
Linfocitos B , Linfoma de Burkitt , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Proteínas Proto-Oncogénicas c-myc , Latencia del Virus , Animales , Linfoma de Burkitt/virología , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patología , Linfoma de Burkitt/genética , Humanos , Ratones , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/metabolismo , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Herpesvirus Humano 4/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Linfocitos B/virología , Linfocitos B/metabolismo , Antígenos Nucleares del Virus de Epstein-Barr/metabolismo , Antígenos Nucleares del Virus de Epstein-Barr/genética , Apoptosis , Proteínas Virales/metabolismo , Proteínas Virales/genéticaRESUMEN
We previously showed that MYC promoted Burkitt lymphoma (BL) growth by inhibiting the tumor suppressor miR-150, resulting in release of miR-150 targets MYB and ZDHHC11. The ZDHHC11 gene encodes three different transcripts including a mRNA (pcZDHHC11), a linear long non-coding RNA (lncZDHHC11) and a circular RNA (circZDHHC11). All transcripts contain the same region with 18 miR-150 binding sites. Here we studied the relevance of circZDHHC11, including this miR-150 binding site region, for growth of BL cells. CircZDHHC11 was mainly present in the cytoplasmic fraction in BL cells and its localization was not altered upon miR-150 overexpression. Knockdown of circZDHHC11 caused a strong inhibition of BL growth without affecting the expression levels of MYC, MYB, miR-150 and other genes. Overexpression of circZDHHC11 neither affected cell growth, nor rescued the phenotype induced by miR-150 overexpression. Genomic deletion of the miR-150 binding site region did not affect growth, nor did it change the effect of circZDHHC11 knockdown. This indicated that the miR-150 binding site region is dispensable for the growth promoting role of circZDHHC11. To conclude, our results show that circZDHHC11 is a crucial factor supporting BL cell growth independent of its ability to sponge miR-150.
Asunto(s)
Linfoma de Burkitt , MicroARNs , Humanos , Linfoma de Burkitt/patología , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , ARN Mensajero/genética , ARN CircularRESUMEN
Epstein-Barr virus (EBV) contributes to the development of a significant subset of human lymphomas. As a herpes virus, EBV can transition between a lytic state which is required to establish infection and a latent state where a limited number of viral antigens are expressed which allows infected cells to escape immune surveillance. Three broad latency programs have been described which are defined by the expression of viral proteins RNA, with latency I being the most restrictive expressing only EBV nuclear antigen 1 (EBNA1) and EBV-encoded small RNAs (EBERs) and latency III expressing the full panel of latent viral genes including the latent membrane proteins 1 and 2 (LMP1/2), and EBNA 2, 3, and leader protein (LP) which induce a robust T-cell response. The therapeutic use of EBV-specific T-cells has advanced the treatment of EBV-associated lymphoma, however this approach is only effective against EBV-associated lymphomas that express the latency II or III program. Latency I tumors such as Burkitt lymphoma (BL) and a subset of diffuse large B-cell lymphomas (DLBCL) evade the host immune response to EBV and are resistant to EBV-specific T-cell therapies. Thus, strategies for inducing a switch from the latency I to the latency II or III program in EBV+ tumors are being investigated as mechanisms to sensitize tumors to T-cell mediated killing. Here, we review what is known about the establishment and regulation of latency in EBV infected B-cells, the role of EBV-specific T-cells in lymphoma, and strategies to convert latency I tumors to latency II/III.
Asunto(s)
Linfoma de Burkitt , Infecciones por Virus de Epstein-Barr , Infección Latente , Linfoma de Células B Grandes Difuso , Humanos , Herpesvirus Humano 4 , Infecciones por Virus de Epstein-Barr/complicaciones , Latencia del Virus , Linfoma de Burkitt/patología , Proteínas Virales/genética , Linfoma de Células B Grandes Difuso/patologíaRESUMEN
INTRODUCTION: The role of age and sex in the presentation and outcome of endemic Burkitt lymphoma (BL) has not been studied recently. This study analysed these factors in 934 patients with BL who had received cyclophosphamide and intrathecal methotrexate as treatment. METHODS: Records of 934 children diagnosed with BL from 2004 to 2015 were obtained from our Paediatric Oncology Networked Database (POND) cancer registry. Age at diagnosis, sex, disease stage, time to diagnosis, delay in diagnosis, completion of treatment, rate of abandonment, and one-year survival rates were recorded and statistically analysed. RESULTS: The male to female ratio of 1.41 for the study population of 934. The median delay from onset of symptoms to diagnosis was 31 days. The St Jude stage distribution was I = 6.4%, II = 5.9%, III = 71.5% and IV = 16.2%. Significantly more patients presented with stage III disease in age groups 5-9 and 10-14 years than 0-4 years. The overall 1-year survival rate was 53.45%, respectively 77.1% for stage I, 67.9% for stage II, 55.1% for stage III and 32.4% for stage IV disease (p<0.001). There was no significant difference in survival by sex and age group. CONCLUSION: Patients aged under 5 years presented with less-advanced disease, but survival was not affected by age. Sex did not influence delay to diagnosis and overall survival. The long delay between the onset of symptoms and diagnosis emphasises the need for interventions to achieve an earlier diagnosis and a better survival rate.
Asunto(s)
Linfoma de Burkitt , Niño , Humanos , Masculino , Femenino , Anciano , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/patología , Camerún , Ciclofosfamida/uso terapéutico , Metotrexato/uso terapéutico , Supervivencia sin Enfermedad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del TratamientoRESUMEN
Dimeric naphthopyranones are known to be biologically active, however, for the corresponding monomeric naphthopyranones this information is still elusive. Here the first enantioselective total synthesis of semi-viriditoxic acid as well as the synthesis of semi-viriditoxin and derivatives is reported. The key intermediate in the synthesis of naphthopyranones is an α,ß-unsaturated δ-lactone, which we synthesized in two different ways (Ghosez-cyclization and Grubbs ring-closing metathesis), while the domino-Michael-Dieckmann reaction of the α,ß-unsaturated δ-lactone with an orsellinic acid derivative is the key reaction. A structure-activity relationship study was performed measuring the cytotoxicity in Burkitt B lymphoma cells (Ramos). The dimeric structure was found to be crucial for biological activity: Only the dimeric naphthopyranones showed cytotoxic and apoptotic activity, whereas the monomers did not display any activity at all.
Asunto(s)
Antineoplásicos , Linfoma de Burkitt , Relación Estructura-Actividad , Línea Celular Tumoral , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/patología , Estereoisomerismo , Apoptosis/efectos de los fármacos , Lactonas/química , Lactonas/farmacología , Lactonas/síntesis química , CiclizaciónRESUMEN
Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation that tumours exploit to counteract phospholipid oxidation1,2. Here, we identify proferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected prosurvival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high concentrations of 7-DHC are cytotoxic to developing neurons by favouring lipid peroxidation3, we now show that 7-DHC accumulation confers a robust prosurvival function in cancer cells. Because of its far superior reactivity towards peroxyl radicals, 7-DHC effectively shields (phospho)lipids from autoxidation and subsequent fragmentation. We provide validation in neuroblastoma and Burkitt's lymphoma xenografts where we demonstrate that the accumulation of 7-DHC is capable of inducing a shift towards a ferroptosis-resistant state in these tumours ultimately resulting in a more aggressive phenotype. Conclusively, our findings provide compelling evidence of a yet-unrecognized antiferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.
Asunto(s)
Linfoma de Burkitt , Deshidrocolesteroles , Ferroptosis , Neuroblastoma , Animales , Humanos , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patología , Supervivencia Celular , Deshidrocolesteroles/metabolismo , Peroxidación de Lípido , Trasplante de Neoplasias , Neuroblastoma/metabolismo , Neuroblastoma/patología , Oxidación-Reducción , Fenotipo , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Burkitt lymphoma (BL) is a subtype of non-Hodgkin lymphoma. It is strongly associated with HIV infection and has a highly aggressive clinical course. The involvement of the maxillofacial region in BL has rarely been reported. CASE DESCRIPTION: A 36-year-old woman with HIV-positive status had painless bilateral swelling of the oral mucosa and middle and lower thirds of the face. Microscopic analysis of the oral lesion revealed an atypical lymphoid infiltrate with a starry sky pattern. The lymphoid cells expressed cluster of differentiation 20, cluster of differentiation 10, B-cell lymphoma 6, and c-Myc; the Ki-67 proliferative index was high. The tumor cells were positive for Epstein-Barr virus. These results led to the diagnosis of HIV-related BL. PRACTICAL IMPLICATIONS: BL and other immunodeficiency-related lymphoproliferative malignancies may affect the oral and maxillofacial regions and should be included in the differential diagnosis of rapidly expanding swelling in young patients.
Asunto(s)
Linfoma de Burkitt , Infecciones por Virus de Epstein-Barr , Infecciones por VIH , Femenino , Humanos , Adulto , Linfoma de Burkitt/complicaciones , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/patología , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/patología , Herpesvirus Humano 4 , Infecciones por VIH/complicaciones , Infecciones por VIH/diagnósticoRESUMEN
CD19 is frequently targeted for immunotherapy in B cell malignancies, which may result in loss of CD19 expression in leukemic cells as an escape mechanism. Stage 0 hematogones (Hgs) are normal CD19-negative very early B cell precursors that can be potentially mistaken for CD19 negative residual leukemic cells by flow cytometry (FCM) in B cell acute lymphoblastic leukemia (BCP-ALL) cases treated with anti CD19 therapy. Our main objective was to characterize and study the incidence of stage 0 hematogones in follow-up bone marrow samples of pediatric BCP-ALL cases. We analyzed the flow cytometry standard files of 61 pediatric BCP-ALL cases treated with conventional chemotherapy and targeted anti-CD19 therapy, for identifying the residual disease and normal B cell precursors including stage 0 Hgs. A non-CD19 alternate gating strategy was used to isolate the B cells for detecting the residual disease and stage 0 Hgs. The stage 0 Hgs were seen in 95% of marrow samples containing CD19+ Hgs. When compared with controls and posttransplant marrow samples, the fraction of stage 0 Hgs was higher in patients receiving anti CD19 therapy (p = 0.0048), but it was not significant when compared with patients receiving chemotherapy (p = 0.1788). Isolated stage 0 Hgs are found in samples treated with anti-CD19 therapy simulating CD19 negative residual illness. Our findings aid in understanding the stage 0 Hgs and its association with CD19+ Hgs in anti CD19 therapy and conventional chemotherapy. This is crucial as it can be potentially mistaken for residual disease in patients treated with anti CD19 therapy.