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Deficient (d) DNA mismatch repair (MMR) is a biomarker predictive of better response to PD-1 blockade immunotherapy in solid tumors. dMMR can be caused by mutations in MMR genes or by protein inactivation, which can be detected by sequencing and immunohistochemistry, respectively. To investigate the role of dMMR in diffuse large B-cell lymphoma (DLBCL), MMR gene mutations and expression of MSH6, MSH2, MLH1, and PMS2 proteins were evaluated by targeted next-generation sequencing and immunohistochemistry in a large cohort of DLBCL patients treated with standard chemoimmunotherapy, and correlated with the tumor immune microenvironment characteristics quantified by fluorescent multiplex immunohistochemistry and gene-expression profiling. The results showed that genetic dMMR was infrequent in DLBCL and was significantly associated with increased cancer gene mutations and favorable immune microenvironment, but not prognostic impact. Phenotypic dMMR was also infrequent, and MMR proteins were commonly expressed in DLBCL. However, intratumor heterogeneity existed, and increased DLBCL cells with phenotypic dMMR correlated with significantly increased T cells and PD-1+ T cells, higher average nearest neighbor distance between T cells and PAX5+ cells, upregulated immune gene signatures, LE4 and LE7 ecotypes and their underlying Ecotyper-defined cell states, suggesting the possibility that increased T cells targeted only tumor cell subsets with dMMR. Only in patients with MYC¯ DLBCL, high MSH6/PMS2 expression showed significant adverse prognostic effects. This study shows the immunologic and prognostic effects of genetic/phenotypic dMMR in DLBCL, and raises a question on whether DLBCL-infiltrating PD-1+ T cells target only tumor subclones, relevant for the efficacy of PD-1 blockade immunotherapy in DLBCL.
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Reparación de la Incompatibilidad de ADN , Linfoma de Células B Grandes Difuso , Microambiente Tumoral , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/patología , Reparación de la Incompatibilidad de ADN/genética , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Masculino , Femenino , Mutación , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Pronóstico , Adulto , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismoRESUMEN
Lymphoma is a highly heterogeneous lymphohematopoietic tumor. As our understanding of the biological and pathological characteristics of lymphoma improves, we are identifying an increasing number of lymphoma subtypes. Genotyping has enhanced our ability to diagnose, treat, and monitor the prognosis of lymphoma. Despite significant improvements in treatment effectiveness, traditional methods for assessing disease response and monitoring prognosis are imperfect, and there is no significant improvement in overall remission rates for lymphoma patients. Minimal Residual Disease (MRD) is often indicative of refractory disease or early relapse. For lymphoma patients, personalized MRD monitoring techniques offer an efficient means to estimate disease remission levels, predict early relapse risk, and assess the effectiveness of new drug regimens. In this review, we delve into the MRD procedures in lymphoma, including sample selection and requirements, detection methods and their limitations and advantages, result interpretation. Besides, we also introduce the clinical applications of MRD detection in lymphoma.
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Linfoma , Neoplasia Residual , Neoplasia Residual/diagnóstico , Humanos , Linfoma/diagnóstico , Pronóstico , Biomarcadores de Tumor , Relevancia ClínicaRESUMEN
Diffuse large B-cell lymphoma (DLBCL) represents the most common tumor in non-Hodgkin's lymphoma. N-Myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor highly expressed in healthy tissues but downregulated in many cancers. Although cell proliferation-related metabolism rewiring has been well characterized, less is known about the mechanism of metabolic changes with DLBCL. Herein, we investigated the expressions of NDRG2, MYC and Myc-interacting zinc finger protein 1 (MIZ-1) in seven human lymphoma (mostly DLBCLs) cell lines. NDRG2 expression was inversely correlated with the expressions of MYC and MIZ-1. Further, we explored the regulatory mechanism and biological functions underlying the lymphomagenesis involving NDRG2, MYC and MIZ-1. MYC and MIZ-1 promoted DLBCL cell proliferation, while NDRG2 induced apoptosis in LY8 cells. Moreover, NDRG2 methylation was reversed by the 5-Aza-2'-deoxycytidine (5-Aza-CDR) treatment, triggering the downregulation of MYC and inhibiting DLBCL cell survival. MYC interacts with NDRG2 to regulate energy metabolism associated with mTOR. Remarkably, supporting the biological significance, the converse correlation between NDRG2 and MYC was observed in human DLBCL tumor tissues (R = -0.557). Bioinformatics analysis further validated the association among NDRG2, MYC, MIZ-1, mTOR, and related metabolism genes. Additionally, NDRG2 (P = 0.001) and MYC (P < 0.001) were identified as promising prognostic biomarkers in DLBCL patients through survival analysis. Together, our data demonstrate that the MYC/MIZ-1 complex interplays with NDRG2 to influence the proliferation and apoptosis of DLBCL cells and show the characterizations of NDRG2, MYC and MIZ-1 for metabolism features and prediction prognosis in DLBCL.
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Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso , Proteínas Proto-Oncogénicas c-myc , Proteínas Supresoras de Tumor , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Masculino , Pronóstico , Línea Celular Tumoral , Femenino , Persona de Mediana Edad , Metilación de ADN , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Anciano , Proliferación Celular , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismoRESUMEN
BACKGROUND: p53, the most frequently mutated gene in cancer, lacks effective targeted drugs. METHODS: We developed monoclonal antibodies (mAbs) that target a p53 hotspot mutation E285K without cross-reactivity with wild-type p53. They were delivered using lipid nanoparticles (LNPs) that encapsulate DNA plasmids. Western blot, BLI, flow cytometry, single-cell sequencing (scRNA-seq), and other methods were employed to assess the function of mAbs in vitro and in vivo. RESULTS: These LNP-pE285K-mAbs in the IgG1 format exhibited a robust anti-tumor effect, facilitating the infiltration of immune cells, including CD8+ T, B, and NK cells. scRNA-seq revealed that IgG1 reduces immune inhibitory signaling, increases MHC signaling from B cells to CD8+ T cells, and enriches anti-tumor T cell and B cell receptor profiles. The E285K-mAbs were also produced in the dimeric IgA (dIgA) format, whose anti-tumor activity depended on the polymeric immunoglobulin receptor (PIGR), a membrane Ig receptor, whereas that of IgG1 relied on TRIM21, an intracellular IgG receptor. CONCLUSIONS: Targeting specific mutant epitopes using DNA-encoded and LNP-delivered mAbs represents a potential precision medicine strategy against p53 mutants in TRIM21- or PIGR-positive cancers.
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Anticuerpos Monoclonales , Mutación , Proteína p53 Supresora de Tumor , Proteína p53 Supresora de Tumor/inmunología , Proteína p53 Supresora de Tumor/genética , Animales , Humanos , Ratones , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Neoplasias/inmunología , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Linfocitos T CD8-positivos/inmunología , Nanopartículas/química , Línea Celular TumoralRESUMEN
OBJECTIVE: Recent studies have found a high prevalence of hepatitis B virus (HBV) infection in patients with non-Hodgkin's lymphoma (NHL), especially B-cell non-Hodgkin's lymphoma (B-NHL). However, most studies did not classify it and analyze the correlation between HBV and its various subtypes. METHODS: The authors retrospectively analyzed 1424 patients with lymphoma. Differences in the prevalence of HBV infection in patients with different pathological types of lymphoma were analyzed. The clinical characteristics, progression-free survival (PFS), and overall survival (OS) of HBV-positive and negative B-NHL subtypes were compared according to HBV infection. RESULTS: The HBV infection rate in NHL patients was 7.65%, which was higher than that in HL patients (2.59%, p < 0.05). The HBV infection rate in the B-NHL was higher than that in the T-cell non-Hodgkin's lymphoma (T-NHL) (8.14% vs. 4.95%). The HBV infection rate in the aggressive B-NHL was similar to that of the indolent B-NHL (8.30% vs. 7.88%), and the highest HBV infection rates were found in diffuse large B-cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, but no significant differences in clinical characteristics, PFS, and OS were seen between HBV-positive and negative patients in the two subtypes. CONCLUSIONS: There was an association between HBV infection and the development of NHL and HBV infection may play a role in the pathogenesis of B-NHL, but not T-NHL.
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Virus de la Hepatitis B , Hepatitis B , Humanos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Hepatitis B/complicaciones , Hepatitis B/virología , Hepatitis B/epidemiología , Adulto , Anciano , Virus de la Hepatitis B/aislamiento & purificación , Adulto Joven , Prevalencia , Linfoma no Hodgkin/virología , Linfoma no Hodgkin/epidemiología , Adolescente , Anciano de 80 o más Años , Linfoma de Células B/virología , Linfoma de Células B/epidemiología , Linfoma de Células B/patología , Linfoma de Células B/mortalidad , Supervivencia sin ProgresiónRESUMEN
Objective: The development of diffuse large B-cell lymphoma (DLBCL) is closely related to the host infection status. China is a highly endemic area for hepatitis B virus (HBV) infection. It is not clear whether HBV infection has a consistent effect on the prognostic implications of patients with DLBCL in different treatment settings. Materials and methods: We conducted a cohort study of 692 patients with DLBCL receiving three or more cycles of treatment with a CHOP or R-CHOP regimen from the First Hospital of Jilin University between July 2011 and July 2022. The patients were divided into two groups based on their hepatitis B surface antigen (HBsAg) status: HBsAg-positive (n = 84, 12.1%) and HBsAg-negative (n = 608, 87.9%) groups. Tumor specimens from 180 patients with primary DLBCL were collected for next-generation sequencing (NGS). Results: The HBsAg-positive group had more frequent abnormal liver function (P = 0.003), hypoalbuminemia (P < 0.001), incidence of > 2 extranodal organs (P = 0.011), and spleen involvement (P < 0.001) than the HBsAg-negative group. HBsAg-positive patients had lower complete response (CR) and overall response rates (ORR) rates (all the p values < 0.05), in either the CHOP group or R-CHOP group. Among patients receiving R-CHOP, the rates of disease progression within 12 and 24 months were higher in the HBsAg-positive group than in the HBsAg-negative group (P=0.018, P=0.029). However, no significant difference in disease progression was observed between HBsAg-positive and HBsAg-negative patients in the CHOP group(P > 0.05). HBsAg positivity (OS: HR [95% CI] = 2.511 [1.214-5.192], P = 0.013) was only associated with poorer OS in the CHOP group. Whereas in the R-CHOP group, HBsAg positivity was associated with both poorer OS and PFS (OS: HR [95% CI] = 1.672 [1.050-2.665], P = 0.030; PFS: HR [95% CI] = 1.536 [1.013-2.331], P = 0.043). Additionally, HBsAg-positive patients with DLBCL also had a higher prevalence of mutations in MYC, ATM, PTPN6, and epigenetically regulated genes. Conclusion: These findings suggest that HBsAg-positive DLBCL patients may represent a distinct subgroup with a poorer prognosis. The standard therapies may be insufficient and new therapeutic strategies should be developed based on a better understanding of the underlying mechanisms of chemoresistance.
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Antígenos de Superficie de la Hepatitis B , Linfoma de Células B Grandes Difuso , Humanos , Estudios de Cohortes , Ciclofosfamida/uso terapéutico , Progresión de la Enfermedad , Doxorrubicina/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Prednisona/uso terapéutico , Rituximab/uso terapéutico , Vincristina/uso terapéuticoRESUMEN
Introduction: Our previous studies have demonstrated that tumor-infiltrating lymphocytes (TILs), including normal B cells, T cells, and natural killer (NK) cells, in diffuse large B-cell lymphoma (DLBCL) have a significantly favorable impact on the clinical outcomes of patients treated with standard chemoimmunotherapy. In this study, to gain a full overview of the tumor immune microenvironment (TIME), we assembled a flow cytometry cohort of 102 patients diagnosed with DLBCL at the Duke University Medical Center. Methods: We collected diagnostic flow cytometry data, including the proportion of T cells, abnormal B cells, normal B cells, plasma cells, NK cells, monocytes, and granulocytes in fresh biopsy tissues at clinical presentation, and analyzed the correlations with patient survival and between different cell populations. Results: We found that low T cell percentages in all viable cells and low ratios of T cells to abnormal B cells correlated with significantly poorer survival, whereas higher percentages of normal B cells among total B cells (or high ratios of normal B cells to abnormal B cells) and high percentages of NK cells among all viable cells correlated with significantly better survival in patients with DLBCL. After excluding a small number of patients with low T cell percentages, the normal B cell percentage among all B cells, but not T cell percentage among all cells, continued to show a remarkable prognostic effect. Data showed significant positive correlations between T cells and normal B cells, and between granulocytes and monocytes. Furthermore, we constructed a prognostic model based on clinical and flow cytometry factors, which divided the DLBCL cohort into two equal groups with remarkable differences in patient survival and treatment response. Summary: TILs, including normal B cells, T cells, and NK cells, are associated with favorable clinical outcomes in DLBCL, and flow cytometry capable of quantifying the TIME may have additional clinical utility for prognostication.
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Linfocitos Infiltrantes de Tumor , Linfoma de Células B Grandes Difuso , Humanos , Citometría de Flujo , Linfoma de Células B Grandes Difuso/patología , Linfocitos T/patología , Monocitos , Microambiente TumoralRESUMEN
Over the past decades, significant strides have been made in understanding the pathobiology, prognosis, and treatment options for mantle cell lymphoma (MCL). The heterogeneity observed in MCL's biology, genomics, and clinical manifestations, including indolent and aggressive forms, is intricately linked to factors such as the mutational status of the variable region of the immunoglobulin heavy chain gene, epigenetic profiling, and Sox11 expression. Several intriguing subtypes of MCL, such as Cyclin D1-negative MCL, in situ mantle cell neoplasm, CCND1/IGH FISH-negative MCL, and the impact of karyotypic complexity on prognosis, have been explored. Notably, recent immunochemotherapy regimens have yielded long-lasting remissions in select patients. The therapeutic landscape for MCL is continuously evolving, with a shift towards nonchemotherapeutic agents like ibrutinib, acalabrutinib, and venetoclax. The introduction of BTK inhibitors has brought about a transformative change in MCL treatment. Nevertheless, the challenge of resistance to BTK inhibitors persists, prompting ongoing efforts to discover strategies for overcoming this resistance. These strategies encompass non-covalent BTK inhibitors, immunomodulatory agents, BCL2 inhibitors, and CAR-T cell therapy, either as standalone treatments or in combination regimens. Furthermore, developing novel drugs holds promise for further improving the survival of patients with relapsed or refractory MCL. In this comprehensive review, we methodically encapsulate MCL's clinical and pathological attributes and the factors influencing prognosis. We also undertake an in-depth examination of stratified treatment alternatives. We investigate conceivable resistance mechanisms in MCL from a genetic standpoint and offer precise insights into various therapeutic approaches for relapsed or refractory MCL.
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Antineoplásicos , Linfoma de Células del Manto , Humanos , Adulto , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Pronóstico , GenómicaAsunto(s)
Anticuerpos Monoclonales Humanizados , Linfoma Extranodal de Células NK-T , Linfoma de Células T , Humanos , Pronóstico , Biomarcadores de Tumor , Células Asesinas Naturales/patología , Linfoma Extranodal de Células NK-T/tratamiento farmacológico , Linfoma Extranodal de Células NK-T/patología , Estudios RetrospectivosRESUMEN
Lymphoma is the sixth most common type of cancer worldwide. Under the current treatment standards, patients with lymphoma often fail to respond to treatment or relapse early and require further therapy. Hence, novel therapeutic strategies need to be explored and our understanding of the molecular underpinnings of lymphomas should be expanded. Ferroptosis, a non-apoptotic regulated cell death, is characterized by increased reactive oxygen species and lipid peroxidation due to metabolic dysfunction. Excessive or lack of ferroptosis has been implicated in tumor development. Current preclinical evidences suggest that ferroptosis participates in tumorigenesis, progression, and drug resistance of lymphoma, identifying a potential biomarker and an attractive molecular target. Our review summarizes the core mechanisms and regulatory networks of ferroptosis and discusses existing evidences of ferroptosis induction for the treatment of lymphoma, with intent to provide a framework for understanding the role of ferroptosis in lymphomagenesis and a new perspective of lymphoma treatment.
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Ferroptosis , Linfoma , Muerte Celular Regulada , Humanos , Ferroptosis/genética , Linfoma/tratamiento farmacológico , Linfoma/genética , Carcinogénesis , Transformación Celular Neoplásica , Peroxidación de LípidoRESUMEN
PURPOSE: Tumor-infiltrating B lymphocytes (TIL-B) have demonstrated prognostic and predictive significance in solid cancers. In this study, we aimed to distinguish TIL-Bs from malignant B-cells in diffuse large B-cell lymphoma (DLBCL) and determine the clinical and biological significance. EXPERIMENTAL DESIGN: A total of 269 patients with de novo DLBCL from the International DLBCL R-CHOP Consortium Program were studied. Ultra-deep sequencing of the immunoglobulin genes was performed to determine B-cell clonotypes. The frequencies and numbers of TIL-B clonotypes in individual repertoires were correlated with patient survival, gene expression profiling (GEP) data, and frequencies of DLBCL-infiltrating immune cells quantified by fluorescent multiplex IHC at single-cell resolution. RESULTS: TIL-B abundance, evaluated by frequencies of normal B-cell clonotypes in the immunoglobulin repertoires, remarkably showed positive associations with significantly better survival of patients in our sequenced cohorts. DLBCLs with high versus low TIL-B abundance displayed distinct GEP signatures, increased pre-memory B-cell state and naïve CD4 T-cell state fractions, and higher CD4+ T-cell infiltration. TIL-B frequency, as a new biomarker in DLBCL, outperformed the germinal center (GC) B-cell-like/activated B-cell-like classification and TIL-T frequency. The identified TIL-B-high GEP signature, including genes upregulated during T-dependent B-cell activation and those highly expressed in normal GC B cells and T cells, showed significant favorable prognostic effects in several external validation cohorts. CONCLUSIONS: TIL-B frequency is a significant prognostic factor in DLBCL and plays a crucial role in antitumor immune responses. This study provides novel insights into the prognostic determinants in DLBCL and TIL-B functions with important therapeutic implications.
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Linfocitos B , Linfoma de Células B Grandes Difuso , Humanos , Pronóstico , Linfocitos B/metabolismo , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Inmunidad , Inmunoglobulinas/metabolismoRESUMEN
[This corrects the article DOI: 10.3389/fcell.2021.762796.].
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Mantle cell lymphoma (MCL) is a lethal hematological malignancy with a median survival of 4 years. Its lethality is mainly attributed to a limited understanding of clinical tumor progression and resistance to current therapeutic regimes. Intrinsic, prolonged drug treatment and tumor-microenvironment (TME) facilitated factors impart pro-tumorigenic and drug-insensitivity properties to MCL cells. Hence, elucidating neoteric pharmacotherapeutic molecular targets involved in MCL progression utilizing a global "unified" analysis for improved disease prevention is an earnest need. Using integrated transcriptomic analyses in MCL patients, we identified a Fibroblast Growth Factor Receptor-1 (FGFR1), and analyses of MCL patient samples showed that high FGFR1 expression was associated with shorter overall survival in MCL patient cohorts. Functional studies using pharmacological intervention and loss of function identify a novel MYC-EZH2-CDKN1C axis-driven proliferation in MCL. Further, pharmacological targeting with erdafitinib, a selective small molecule targeting FGFRs, induced cell-cycle arrest and cell death in-vitro, inhibited tumor progression, and improved overall survival in-vivo. We performed extensive pre-clinical assessments in multiple in-vivo model systems to confirm the therapeutic potential of erdafitinib in MCL and demonstrated FGFR1 as a viable therapeutic target in MCL.
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Linfoma de Células del Manto , Adulto , Humanos , Muerte Celular , Línea Celular Tumoral , Proliferación Celular , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/metabolismo , Receptores de Factores de Crecimiento de Fibroblastos , Transducción de Señal , Microambiente Tumoral/genéticaRESUMEN
The transcriptional factor ETS1 is upregulated in 25% of diffuse large B cell lymphoma (DLBCL). Here, we studied the role of ETS1 phosphorylation at threonine 38, a marker for ETS1 activation, in DLBCL cellular models and clinical specimens. p-ETS1 was detected in activated B cell-like DLBCL (ABC), not in germinal centre B-cell-like DLBCL (GCB) cell lines and, accordingly, it was more common in ABC than GCB DLBCL diagnostic biopsies. MEK inhibition decreased both baseline and IgM stimulation-induced p-ETS1 levels. Genetic inhibition of phosphorylation of ETS1 at threonine 38 affected the growth and the BCR-mediated transcriptome program in DLBCL cell lines. Our data demonstrate that ETS1 phosphorylation at threonine 38 is important for the growth of DLBCL cells and its pharmacological inhibition could benefit lymphoma patients.
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Diffuse large B-cell lymphoma (DLBCL) can be cured with standard front-line immunochemotherapy, whereas nearly 30-40% of patients experience refractory or relapse. For several decades, the standard treatment strategy for fit relapsed/refractory (R/R) DLBCL patients has been high-dose chemotherapy followed by autologous hematopoietic stem cell transplant (auto-SCT). However, the patients who failed in salvage treatment or those ineligible for subsequent auto-SCT have dismal outcomes. Several immune-based therapies have been developed, including monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engaging antibodies, chimeric antigen receptor T-cells, immune checkpoint inhibitors, and novel small molecules. Meanwhile, allogeneic SCT and radiotherapy are still necessary for disease control for fit patients with certain conditions. In this review, to expand clinical treatment options, we summarize the recent progress of immune-related therapies and prospect the future indirections in patients with R/R DLBCL.
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Advanced studies have shown a biological correlation between hepatitis B virus (HBV) and B-cell lymphoma, especially diffuse large B-cell lymphoma (DLBCL). Patients with DLBCL infected with HBV (HBV-associated DLBCL) are clinically characterized by an advanced clinical stage, poor response to front-line immunochemotherapy regimens, and worse clinical prognosis. HBV-associated DLBCL often exhibits abnormal activation of the nuclear factor kappa B pathway as well as mutations in oncogenes, including Myc and BCL-6. Currently, there is no consensus on any specific and effective treatment for HBV-associated DLBCL. Therefore, in this review, we comprehensively and mechanistically analyzed the natural history of HBV infection and immunity, including HBV-mediated oncogenes, immune escape, epigenetic alterations, dysregulated signaling pathways, and potential therapeutic approaches for HBV-associated DLBCL. We hope that an improved understanding of the biology of HBV-associated DLBCL would lead to the development of novel therapeutic approaches, enhance the number of effective clinical trials, and improve the prognosis of this disease.
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Hepatitis B , Linfoma de Células B Grandes Difuso , Humanos , Virus de la Hepatitis B , Pronóstico , Resultado del Tratamiento , Hepatitis B/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patologíaRESUMEN
The blastoid (B) and pleomorphic (P) variants of mantle cell lymphoma (MCL) are associated with aggressive clinical behavior. In this study, we collected 102 cases of B-MCL and P-MCL from untreated patients. We reviewed clinical data, analyzed morphologic features using an image analysis tool (ImageJ) and we assessed mutational and gene expression profiles. The chromatin pattern of lymphoma cells was assessed quantitatively by the pixel value. Cases of B-MCL showed a greater median pixel value with lower variation compared with P-MCL, indicating a homogeneously euchromatin-rich pattern in B-MCL. In addition, the Feret diameter of the nuclei was significantly smaller (median 6.92 vs. 8.49 µm per nucleus, P <0.001) and had a lesser degree of variation in B-MCL compared with P-MCL, indicating that B-MCL cells have smaller cells with a more monomorphic appearance. B-MCL showed a significantly higher median Ki-67 proliferation rate (60% vs. 40%, P =0.003), and affected patients had poorer overall survival compared with those with P-MCL (median overall survival: 3.1 vs. 8.8 y, respectively, P =0.038). NOTCH1 mutation was significantly more frequent in B-MCL compared with P-MCL (33% and 0%, respectively, P =0.004). Gene expression profiling showed 14 genes overexpressed in B-MCL cases and gene set enrichment assay for the overexpressed genes showed significant enrichment in the cell cycle and mitotic transition pathways. We also report a subset of MCL cases that has blastoid chromatin but a higher degree of pleomorphism in nuclear size and shape, designated here as hybrid MCL. Hybrid MCL cases had a similar Ki-67 proliferation rate, mutation profile, and clinical outcome to B-MCL and distinct from P-MCL. In summary, these data suggest biological differences between B-MCL and P-MCL cases justifying their separate designation when possible.
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Linfoma de Células del Manto , Adulto , Humanos , Cromatina , Antígeno Ki-67/análisis , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/patología , MutaciónRESUMEN
Dual expression of MYC and BCL2 proteins (double-expressor lymphoma [DEL]) as well as cell of origin (COO) are important prognostic factors in patients with diffuse large B-cell lymphoma (DLBCL) after conventional chemotherapy. We studied the prognostic impact of DEL and COO in patients with relapsed DLBCL treated with autologous stem cell transplant (ASCT). Three-hundred and three patients with stored tissue samples were identified. Classification was successful in 267 patients: 161 (60%) were DEL/non-double hit (DHL), 98 (37%) were non-DEL/non-DHL, and 8 (3%) were DEL/DHL. Compared to non-DEL/non-DHL, DEL/DHL had worse overall survival while DEL/non-DHL did not significantly differ in overall survival. On multivariable analysis, DEL/DHL, age >60 years, and >2 prior therapies, but not COO, were important prognostic factors for overall survival. When we explored the interaction of COO and BCL2 expression, patients with germinal center B-cell (GCB)/BCL2 (+) had inferior progression-free survival (PFS) compared to GCB/BCL2 (-) patients (HR, 4.97; P = 0.027). We conclude that the DEL/non-DHL and non-DEL/non-DHL subtypes of DLBCL have similar survival after ASCT. The negative impact of GCB/BCL2 (+) on PFS warrants future trials targeting BCL2 after ASCT. The inferior outcomes in DEL/DHL need to be verified in a larger number of patients.
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Relevancia Clínica , Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B Grandes Difuso , Humanos , Persona de Mediana Edad , Autoinjertos , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Proteínas Proto-Oncogénicas c-bcl-2/uso terapéutico , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/análisis , Proteínas Proto-Oncogénicas c-myc/uso terapéuticoRESUMEN
Lymphoma is a heterogeneous group of diseases that often require their metabolism program to fulfill the demand of cell proliferation. Features of metabolism in lymphoma cells include high glucose uptake, deregulated expression of enzymes related to glycolysis, dual capacity for glycolytic and oxidative metabolism, elevated glutamine metabolism, and fatty acid synthesis. These aberrant metabolic changes lead to tumorigenesis, disease progression, and resistance to lymphoma chemotherapy. This metabolic reprogramming, including glucose, nucleic acid, fatty acid, and amino acid metabolism, is a dynamic process caused not only by genetic and epigenetic changes, but also by changes in the microenvironment affected by viral infections. Notably, some critical metabolic enzymes and metabolites may play vital roles in lymphomagenesis and progression. Recent studies have uncovered that metabolic pathways might have clinical impacts on the diagnosis, characterization, and treatment of lymphoma subtypes. However, determining the clinical relevance of biomarkers and therapeutic targets related to lymphoma metabolism is still challenging. In this review, we systematically summarize current studies on metabolism reprogramming in lymphoma, and we mainly focus on disorders of glucose, amino acids, and lipid metabolisms, as well as dysregulation of molecules in metabolic pathways, oncometabolites, and potential metabolic biomarkers. We then discuss strategies directly or indirectly for those potential therapeutic targets. Finally, we prospect the future directions of lymphoma treatment on metabolic reprogramming.