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ABSTRACT: Rearrangements that place the oncogenes MYC, BCL2, or BCL6 adjacent to superenhancers are common in mature B-cell lymphomas. Lymphomas with diffuse large B-cell lymphoma (DLBCL) or high-grade morphology with both MYC and BCL2 rearrangements are classified as high-grade B-cell lymphoma with MYC and BCL2 rearrangements ("double hit"; HGBCL-DH-BCL2) and are associated with aggressive disease and poor outcomes. Although it is established that MYC rearrangements involving immunoglobulin (IG) loci are associated with inferior outcomes relative to those involving other non-IG superenhancers, the frequency of and mechanisms driving IG vs non-IG MYC rearrangements have not been elucidated. Here, we used custom targeted capture and/or whole-genome sequencing to characterize oncogene rearrangements across 883 mature B-cell lymphomas including Burkitt lymphoma, follicular lymphoma, DLBCL, and HGBCL-DH-BCL2 tumors. We demonstrate that, although BCL2 rearrangement topology is consistent across entities, HGBCL-DH-BCL2 have distinct MYC rearrangement architecture relative to tumors with single MYC rearrangements or with both MYC and BCL6 rearrangements (HGBCL-DH-BCL6), including both a higher frequency of non-IG rearrangements and different architecture of MYC::IGH rearrangements. The distinct MYC rearrangement patterns in HGBCL-DH-BCL2 occur on the background of high levels of somatic hypermutation across MYC partner loci in HGBCL-DH-BCL2, creating more opportunity to form these rearrangements. Furthermore, because 1 IGH allele is already disrupted by the existing BCL2 rearrangement, the MYC rearrangement architecture in HGBCL-DH-BCL2 likely reflects selective pressure to preserve both BCL2 and B-cell receptor expression. These data provide new mechanistic explanations for the distinct patterns of MYC rearrangements observed across different lymphoma entities.
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Rearranjo Gênico , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Proto-Oncogênicas c-myc , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologiaRESUMO
Peripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL-not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall survival (OS), with DNMT3A-mutated residues skewed toward the methyltransferase domain and dimerization motif (S881-R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutant PTCL-TBX21 cases, which was further validated using immunohistochemistry. Genomewide methylation analysis of DNMT3A-mutant vs wild-type (WT) PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating interferon-γ (IFN-γ), T-cell receptor signaling, and EOMES (eomesodermin), a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in vivo) and further validated in vitro by ectopic expression of DNMT3A mutants (DNMT3A-R882, -Q886, and -V716, vs WT) in CD8+ T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T cells with DNMT3AR882H mutation. Single-cell RNA sequencing(RNA-seq) analysis of CD3+ T cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance and thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.
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Interferon gama , Linfoma de Células T Periférico , Animais , Interferon gama/genética , Linfoma de Células T Periférico/patologia , Metiltransferases/genética , Camundongos , Mutação , Prognóstico , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
The current clinical management of Extranodal NK/T-cell lymphoma (ENKTL) primarily depends on conventional chemotherapy and radiotherapy, underscoring the need for innovative therapeutic strategies. This study explores the clinical significance and therapeutic implication of c-MYC (MYC) in ENKTL. Initially, we identified MYC protein overexpression in approximately 75% of cases within a large cohort of 111 patients. MYC overexpression was strongly correlated with lymphoma cell proliferation and poor clinical outcomes. Intriguingly, integrating MYC expression into the PINK-E prognostic model significantly enhanced its predictive power. Subsequently, we implemented MYC knockdown (KD) in NK malignancy cell lines with MYC overexpression, resulting in significant viability reduction. RNA-sequencing (RNA-seq) used to determine MYC function revealed a high overlap with canonical MYC-regulated genes and enrichment in metabolism and cell cycle regulation. Integrative analysis of the RNA-seq data upon MYC KD with gene expression profiles of primary ENKTL cases identified a subset of genes closely associated with MYC overexpression. Among these, CDK4 emerged as a potential therapeutic target, and its inhibition not only abrogated MYC function but also decreased MYC expression in NK malignancy cells. Furthermore, the clinical-grade CDK4/6 inhibitor palbociclib exhibited a potent anti-tumor effect in xenograft mouse models, especially when combined with gemcitabine. In summary, our study firmly establishes MYC as an oncogene with prognostic significance in ENKTL and highlights CDK4 inhibition as a promising therapeutic strategy for treating ENKTL with MYC overexpression.
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Non-Hodgkin lymphoma (NHL) is composed of a heterogeneous collection of subtypes with considerable differences in genetics, biology and aetiology. Studies to date on physical activity and NHL risk have not had sufficient sample size to evaluate whether associations differ by subtype. We pooled data from nine case-control studies to examine the association between moderate-to-vigorous intensity physical activity (MVPA) and risk of NHL overall and by subtype (diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia/small lymphocytic lymphoma, marginal zone lymphoma and mature T-cell lymphoma). A total of 5653 cases and 9115 controls were included in the pooled analysis. Physical activity was harmonised across nine studies and modelled as study-specific tertiles. Multinomial logistic regression was used to estimate the association between physical activity and NHL, adjusting for confounders. The overall odds of NHL was 13% lower among participants in the most active tertile of MVPA compared to the least active tertile (adjusted odds ratio = 0.87, 95% CI = 0.80, 0.95). Similar decreases were observed across NHL subtypes. In summary, in this pooled analysis of case-control studies, physical activity was associated with a modest risk reduction for each NHL subtype examined and with overall NHL.
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Linfoma Folicular , Linfoma não Hodgkin , Humanos , Fatores de Risco , Linfoma não Hodgkin/etiologia , Linfoma não Hodgkin/complicações , Linfoma Folicular/epidemiologia , Linfoma Folicular/etiologia , Estudos de Casos e Controles , Exercício FísicoRESUMO
The tumor microenvironment (TME) is important in the pathogenesis and prognosis of lymphoma. Previous studies have demonstrated that features of the diffuse large B-cell lymphoma (DLBCL) TME can be associated with prognosis, but questions remain about the mechanisms underlying these TME features, and the interplay between tumor cells and the local TME. Therefore, we performed multispectral immunofluorescence (mIF) using two 6-color panels to interrogate the cellular proportions of T-cell subsets, macrophages, and natural killer cells in 57 cases of de novo DLBCL treated with R-CHOP chemotherapy. We found that very low CD3+ T-cell proportion and low CD4+PD1+ and CD8+PD1+ T cells have poor survival compared to those with a high T-cell proportion. Also, cases with concurrently low TIM3 and PD1 have a poor prognosis. This poor prognosis with low T-cell proportion was validated using immune deconvolution of gene expression profiling data from 351 cases of DLBCL and an additional cohort of 53 cases of DLBCL using routine immunohistochemistry. In addition, cases with loss of B2M, HLA I and/or HLA II protein expression on the tumor cells also had a low T-cell proportion, providing evidence that lack of these proteins allows for immune evasion. Overall, our results show that patients with DLBCL with a low T-cell proportion in the TME have a poor survival when treated with R-CHOP and exhibit mechanisms of immune escape.
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Linfoma Difuso de Grandes Células B , Microambiente Tumoral , Humanos , Microambiente Tumoral/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Prognóstico , Linfócitos T CD8-Positivos/metabolismo , Subpopulações de Linfócitos T/metabolismoRESUMO
BACKGROUND: The relationship between immune checkpoint status and disease outcome is a major focus of research in cutaneous T-cell lymphoma (CTCL), a disfiguring neoplastic dermatological disorder. Mycosis fungoides (MF) and Sézary syndrome (SS) are the two most common types of CTCL. OBJECTIVES: The aim was to evaluate the immune checkpoint markers programmed death protein 1 (PD1), inducible T-cell co-stimulator (ICOS) and programmed death-ligand 1 (PD-L1) in skin biopsies from patients with CTCL relative to disease stage and overall survival. METHODS: This consecutive case series enrolled 47 patients: 57% had stage IA-IIA disease and 43% had stage IIB-IVA2 disease (including seven with SS). RESULTS: PD1, PD-L1 and ICOS expression was seen in all biopsies. Notably, PD-L1 was predominantly expressed on histiocytes/macrophages, but focal expression on CTCL cells was seen. High expression of either ICOS or PD-L1 was associated with advanced-stage disease (P = 0·007 for both) and with the appearance of large-cell transformation (LCT), a histopathological feature associated with a poor prognosis (ICOS: P = 0·02; PD-L1: P = 0·002). PD1 expression was not significantly associated with disease stage (P = 0·12) or LCT (P = 0·49), but expression was high in SS biopsies. A high combined checkpoint marker score (PD1, PD-L1 and ICOS) was associated with advanced-stage disease (P = 0·001), LCT (P = 0·021) and lower overall survival (P = 0·014). CONCLUSIONS: These findings demonstrate the existence of a complex immunoregulatory microenvironment in CTCL and support the development of immunotherapies targeting ICOS and PD-L1 in advanced disease.
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Linfoma Cutâneo de Células T , Micose Fungoide , Síndrome de Sézary , Neoplasias Cutâneas , Antígeno B7-H1/metabolismo , Biomarcadores , Humanos , Proteínas de Checkpoint Imunológico , Proteína Coestimuladora de Linfócitos T Induzíveis , Linfoma Cutâneo de Células T/patologia , Micose Fungoide/patologia , Síndrome de Sézary/patologia , Neoplasias Cutâneas/patologia , Microambiente TumoralRESUMO
ABSTRACT: Primary cutaneous gamma-delta T-cell lymphoma is a rare and aggressive neoplasm, representing less than 1% of all cutaneous T-cell lymphomas. In this article, we report the case of a 49-year-old woman who presented with a history of generalized skin rash and a recent mass on the left upper extremity, as well as right inguinal soft tissue swelling and splenomegaly. Histologic examination of the mass revealed a diffuse subcutaneous infiltrate of large anaplastic and CD30-positive lymphoid cells with rimming of the adipocytes. This case demonstrates unusual cytologic features in primary cutaneous gamma-delta T-cell lymphoma that mimic the features of anaplastic lymphoma kinase-1-negative anaplastic large-cell lymphoma.
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Linfoma Anaplásico de Células Grandes/patologia , Neoplasias Cutâneas/patologia , Diagnóstico Diferencial , Feminino , Humanos , Linfoma Anaplásico de Células Grandes/dietoterapia , Linfoma Cutâneo de Células T/patologia , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias Cutâneas/diagnóstico por imagemRESUMO
Human immunodeficiency virus (HIV)-infected people and solid organ transplant recipients have elevated risk of anaplastic large cell lymphoma (ALCL). Little is known regarding ALCL risk factors in immunosuppressed populations. We used data from US cancer registries linked to HIV registries (1996-2016) and to the national transplant registry (1992-2017). ALCL risk in HIV-infected people and transplant recipients relative to the general population was calculated as a standardized incidence ratio (SIR). ALCL risk factors were evaluated using Poisson regression. We identified 121 incident ALCL cases in the HIV (n = 86) and transplant (n = 35) populations. We reviewed pathology reports for 45 cases and most (86·7%) were confirmed as ALCL. Epstein-Barr virus tested positive in 1/8 (12·5%) cases. Compared to the general population, ALCL risk was strongly elevated among HIV-infected people [SIR 5·43; 95% confidence interval (CI) 4·27-6·81] and transplant recipients (5·96; 4·03-8·49). Among HIV-infected people, ALCL incidence was strongly related to CD4 count [adjusted incidence rate ratio (aIRR) 0·15 for ≥500 vs. <200 cells/µl; P trend < 0·001]. Among transplant recipients, risk was highest within the first year (aIRR 6·82) and 10+ years post-transplant (5·99). In conclusion, ALCL risk is strongly increased in these immunosuppressed populations but may be unrelated to EBV infection based on limited reports.
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Infecções por HIV/complicações , Linfoma Anaplásico de Células Grandes/etiologia , Transplante de Órgãos/efeitos adversos , Transplantados , Adolescente , Adulto , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/complicações , Feminino , Humanos , Hospedeiro Imunocomprometido , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores de Risco , Adulto JovemRESUMO
The neural transcription factor SOX11 is usually highly expressed in typical mantle cell lymphoma (MCL), but it is absent in the more indolent form of MCL. Despite being an important diagnostic marker for this hard-to-treat malignancy, the mechanisms of aberrant SOX11 expression are largely unknown. Herein, we describe 2 modes of SOX11 regulation by the cell-cycle regulator cyclin D1 (CCND1) and the signal transducer and activator of transcription 3 (STAT3). We found that ectopic expression of CCND1 in multiple human MCL cell lines resulted in increased SOX11 transcription, which correlated with increased acetylated histones H3K9 and H3K14 (H3K9/14Ac). Increased H3K9/14Ac and SOX11 expression was also observed after histone deacetylase 1 (HDAC1) or HDAC2 was depleted by RNA interference or inhibited by the HDAC inhibitor vorinostat. Mechanistically, we showed that CCND1 interacted with and sequestered HDAC1 and HDAC2 from the SOX11 locus, leading to SOX11 upregulation. Interestingly, our data revealed a potential inverse relationship between phosphorylated Y705 STAT3 and SOX11 expression in MCL cell lines, primary tumors, and patient-derived xenografts. Functionally, inactivation of STAT3 by inhibiting the upstream Janus kinase (JAK) 1 or JAK2 or by STAT3 knockdown was found to increase SOX11 expression, whereas interleukin-21 (IL-21)-induced STAT3 activation or overexpression of the constitutively active form of STAT3 decreased SOX11 expression. In addition, targeting SOX11 directly by RNA interference or indirectly by IL-21 treatment induced toxicity in SOX11+ MCL cells. Collectively, we demonstrate the involvement of CCND1 and STAT3 in the regulation of SOX11 expression, providing new insights and therapeutic implications in MCL.
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Ciclina D1/metabolismo , Linfoma de Célula do Manto/genética , Fatores de Transcrição SOXC/genética , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatina/metabolismo , Regulação Neoplásica da Expressão Gênica , Loci Gênicos , Células HEK293 , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Histonas/metabolismo , Humanos , Interleucinas/farmacologia , Fosfotirosina/metabolismo , Ligação Proteica , Processamento de Proteína Pós-Traducional , Fatores de Transcrição SOXC/metabolismo , Regulação para Cima/genéticaRESUMO
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell malignancies; approximately one-third of cases are designated as PTCL-not otherwise specified (PTCL-NOS). Using gene-expression profiling (GEP), we have previously defined 2 major molecular subtypes of PTCL-NOS, PTCL-GATA3 and PTCL-TBX21, which have distinct biological differences in oncogenic pathways and prognosis. In the current study, we generated an immunohistochemistry (IHC) algorithm to identify the 2 subtypes in paraffin tissue using antibodies to key transcriptional factors (GATA3 and TBX21) and their target proteins (CCR4 and CXCR3). In a training cohort of 49 cases of PTCL-NOS with corresponding GEP data, the 2 subtypes identified by the IHC algorithm matched the GEP results with high sensitivity (85%) and showed a significant difference in overall survival (OS) (P = .03). The IHC algorithm classification showed high interobserver reproducibility among pathologists and was validated in a second PTCL-NOS cohort (n = 124), where a significant difference in OS between the PTCL-GATA3 and PTCL-TBX21 subtypes was confirmed (P = .003). In multivariate analysis, a high International Prognostic Index score (3-5) and the PTCL-GATA3 subtype identified by IHC were independent adverse predictors of OS (P = .0015). Additionally, the 2 IHC-defined subtypes were significantly associated with distinct morphological features (P < .001), and there was a significant enrichment of an activated CD8+ cytotoxic phenotype in the PTCL-TBX21 subtype (P = .03). The IHC algorithm will aid in identifying the 2 subtypes in clinical practice, which will aid the future clinical management of patients and facilitate risk stratification in clinical trials.
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Biomarcadores Tumorais , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/etiologia , Adulto , Idoso , Algoritmos , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Imunofenotipagem , Linfoma de Células T Periférico/metabolismo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Reprodutibilidade dos TestesRESUMO
Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A /B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2 R172 mutation. CN losses were enriched in genes regulating PI3K-AKT-mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.
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Variações do Número de Cópias de DNA , Linfoma de Células T Periférico/genética , Oncogenes , Feminino , Fator de Transcrição GATA3/genética , Perfilação da Expressão Gênica , Humanos , Linfadenopatia Imunoblástica/genética , Linfoma de Células T Periférico/classificação , Masculino , Mutação , Proteínas com Domínio T/genéticaRESUMO
Insecticide use has been linked to increased risk of non-Hodgkin lymphoma (NHL), however, findings of epidemiologic studies have been inconsistent, particularly for NHL subtypes. We analyzed 1690 NHL cases and 5131 controls in the North American Pooled Project (NAPP) to investigate self-reported insecticide use and risk of NHL overall and by subtypes: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and small lymphocytic lymphoma (SLL). Odds ratios (OR) and 95% confidence intervals for each insecticide were estimated using logistic regression. Subtype-specific associations were evaluated using ASSET (Association analysis for SubSETs). Increased risks of multiple NHL subtypes were observed for lindane (OR = 1.60, 1.20-2.10: FL, DLCBL, SLL), chlordane (OR = 1.59, 1.17-2.16: FL, SLL) and DDT (OR = 1.36, 1.06-1.73: DLBCL, SLL). Positive trends were observed, within the subsets with identified associations, for increasing categories of exposure duration for lindane (Ptrend = 1.7 × 10-4 ), chlordane (Ptrend = 1.0 × 10-3 ) and DDT (Ptrend = 4.2 × 10-3 ), however, the exposure-response relationship was nonlinear. Ever use of pyrethrum was associated with an increased risk of FL (OR = 3.65, 1.45-9.15), and the relationship with duration of use appeared monotonic (OR for >10 years: OR = 5.38, 1.75-16.53; Ptrend = 3.6 × 10-3 ). Our analysis identified several novel associations between insecticide use and specific NHL subtypes, suggesting possible etiologic heterogeneity in the context of pesticide exposure.
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Inseticidas/efeitos adversos , Leucemia Linfocítica Crônica de Células B/epidemiologia , Linfoma Folicular/epidemiologia , Linfoma Difuso de Grandes Células B/epidemiologia , Estudos de Casos e Controles , Clordano/efeitos adversos , DDT/efeitos adversos , Feminino , Hexaclorocicloexano/efeitos adversos , Humanos , Leucemia Linfocítica Crônica de Células B/induzido quimicamente , Modelos Logísticos , Linfoma Folicular/induzido quimicamente , Linfoma Difuso de Grandes Células B/induzido quimicamente , Masculino , Autorrelato , Estados UnidosRESUMO
PURPOSE: The purpose of this study was to investigate associations between pesticide exposures and risk of Hodgkin lymphoma (HL) using data from the North American Pooled Project (NAPP). METHODS: Three population-based studies conducted in Kansas, Nebraska, and six Canadian provinces (HL = 507, Controls = 3886) were pooled to estimate odds ratios and 95% confidence intervals for single (never/ever) and multiple (0, 1, 2-4, ≥ 5) pesticides used, duration (years) and, for select pesticides, frequency (days/year) using adjusted logistic regression models. An age-stratified analysis (≤ 40/ > 40 years) was conducted when numbers were sufficient. RESULTS: In an analysis of 26 individual pesticides, ever use of terbufos was significantly associated with HL (OR: 2.53, 95% CI 1.04-6.17). In age-stratified analyses, associations were stronger among those ≤ 40 years of age. No significant associations were noted among those > 40 years old; however, HL cases ≤ 40 were three times more likely to report ever using dimethoate (OR: 3.76 95% CI 1.02-33.84) and almost twice as likely to have ever used malathion (OR: 1.86 95% CI 1.00-3.47). Those ≤ 40 years of age reporting use of 5 + organophosphate insecticides had triple the odds of HL (OR: 3.00 95% CI 1.28-7.03). Longer duration of use of 2,4-D, ≥ 6 vs. 0 years, was associated with elevated odds of HL (OR: 2.59 95% CI 1.34-4.97). CONCLUSION: In the NAPP, insecticide use may increase the risk of HL, but results are based on small numbers.
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Exposição Ambiental/estatística & dados numéricos , Doença de Hodgkin/epidemiologia , Praguicidas , Adulto , Canadá/epidemiologia , Humanos , Kansas/epidemiologia , Nebraska/epidemiologiaRESUMO
Primary mediastinal large B-cell lymphoma (PMBCL) is recognized as a distinct entity in the World Health Organization classification. Currently, the diagnosis relies on consensus of histopathology, clinical variables, and presentation, giving rise to diagnostic inaccuracy in routine practice. Previous studies have demonstrated that PMBCL can be distinguished from subtypes of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures. However, requirement of fresh-frozen biopsy material has precluded the transfer of gene expression-based assays to the clinic. Here, we developed a robust and accurate molecular classification assay (Lymph3Cx) for the distinction of PMBCL from DLBCL subtypes based on gene expression measurements in formalin-fixed, paraffin-embedded tissue. A probabilistic model accounting for classification error, comprising 58 gene features, was trained on 68 cases of PMBCL and DLBCL. Performance of the model was subsequently evaluated in an independent validation cohort of 158 cases and showed high agreement of the Lymph3Cx molecular classification with the clinicopathological diagnosis of an expert panel (frank misclassification rate, 3.8%). Furthermore, we demonstrate reproducibility of the assay with 100% concordance of subtype assignments at 2 independent laboratories. Future studies will determine Lymph3Cx's utility for routine diagnostic purposes and therapeutic decision making.
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Perfilação da Expressão Gênica , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma não Hodgkin/diagnóstico , Neoplasias do Mediastino/diagnóstico , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/genética , Linfoma não Hodgkin/classificação , Linfoma não Hodgkin/genética , Neoplasias do Mediastino/classificação , Neoplasias do Mediastino/genética , Mediastino/patologia , Inclusão em ParafinaRESUMO
Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding Gα13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assays, that GCB-DLBCL-associated mutations occurring in S1PR2 frequently disrupt the receptor's Akt and migration inhibitory functions. Gα13-deficient mouse germinal centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Gα13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Gα13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the Gα13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of Gα13- and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derived malignancy, Burkitt's lymphoma, also represses germinal centre B-cell growth and promotes confinement via Gα13. These findings identify a Gα13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of germinal centre B cells that is frequently disrupted in germinal centre B-cell-derived lymphoma.
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Linfócitos B/metabolismo , Linfócitos B/patologia , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/metabolismo , Centro Germinativo/patologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Transdução de Sinais , Animais , Sangue/imunologia , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Humanos , Linfa/citologia , Linfoma Difuso de Grandes Células B/genética , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Proteína Oncogênica v-akt/genética , Proteína Oncogênica v-akt/metabolismo , Receptores de Lisoesfingolipídeo/deficiência , Receptores de Lisoesfingolipídeo/genética , Receptores de Lisoesfingolipídeo/metabolismo , Receptores Purinérgicos P2Y/genética , Receptores Purinérgicos P2Y/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/deficiência , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Receptores de Esfingosina-1-FosfatoRESUMO
The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressive lymphomas with poor clinical outcome. High-resolution structural and functional genomic analysis of adult Burkitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene signature (adult-molecularly defined BL [mBL]) revealed the MYC-ARF-p53 axis as the primary deregulated pathway. Adult-mBL had either unique or more frequent genomic aberrations (del13q14, del17p, gain8q24, and gain18q21) compared with pediatric-mBL, but shared commonly mutated genes. Mutations in genes promoting the tonic B-cell receptor (BCR)âPI3K pathway (TCF3 and ID3) did not differ by age, whereas effectors of chronic BCRâNF-κB signaling were associated with adult-mBL. A subset of adult-mBL had BCL2 translocation and mutation and elevated BCL2 mRNA and protein expression, but had a mutation profile similar to mBL. These double-hit lymphomas may have arisen from a tumor precursor that acquired both BCL2 and MYC translocations and/or KMT2D (MLL2) mutation. Gain/amplification of MIR17HG and its paralogue loci was observed in 50% of adult-mBL. In vitro studies suggested miR-17â¼92's role in constitutive activation of BCR signaling and sensitivity to ibrutinib. Overall integrative analysis identified an interrelated gene network affected by copy number and mutation, leading to disruption of the p53 pathway and the BCRâPI3K or NF-κB activation, which can be further exploited in vivo by small-molecule inhibitors for effective therapy in adult-mBL.
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Linfoma de Burkitt/genética , Regulação Neoplásica da Expressão Gênica , Linfoma de Células B/genética , Transcriptoma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/patologia , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Humanos , Imunofenotipagem , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Gradação de Tumores , Adulto JovemRESUMO
PURPOSE: This review will describe and update readers on the recent changes in the 2017 WHO classification regarding peripheral T-cell lymphomas. RECENT FINDINGS: Signficant advances in molecular studies have resulted in revisions to the classification as well as introduction to provisional entities such as breast implant-associated ALCL and nodal PTCL with T-follicular helper phenotype. SUMMARY: Major advances in molecular and gene expression profiling has expanded our knowledge of these rare and aggressive diseases.
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Células Matadoras Naturais , Linfoma de Células T Periférico , Perfilação da Expressão Gênica , Humanos , Linfoma de Células T Periférico/epidemiologia , Linfoma de Células T Periférico/imunologia , Linfoma de Células T Periférico/patologiaRESUMO
Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are associated with resistance to frontline and salvage immunochemotherapy, as well as autologous stem cell transplantation (SCT). We hypothesized that allogeneic SCT (alloSCT) could overcome the chemoresistance associated with DEL/DHL. We retrospectively studied the impact of DEL/DHL status in a multicenter cohort of patients who underwent alloSCT for relapsed/refractory (rel/ref) aggressive B cell non-Hodgkin lymphoma (B-NHL). Seventy-eight patients transplanted at 3 centers in whom tumor tissue was available for immunohistochemistry and fluorescence in situ hybridization were enrolled; 47% had DEL and 13% had DHL. There were no significant differences in 4-year progression-free (PFS) or overall survival (OS) between patients with DEL compared with patients without DEL (PFS 30% versus 39%, P = .24; OS 31% versus 49%, P = .17) or between patients with DHL compared with patients without DHL (PFS 40% versus 34%, P = .62; OS 50% versus 38%, P = .46). The lack of association between DEL or DHL and outcome was confirmed in multivariable models, although inadequate sample size may have limited our ability to detect significant differences. In our cohort alloSCT produced durable remissions in patients with rel/ref aggressive B-NHL irrespective of DEL and DHL status, justifying its consideration in the treatment of patients with rel/ref DEL/DHL.
Assuntos
Leucemia Linfocítica Crônica de Células B , Linfoma de Células B , Neoplasias do Mediastino , Transplante de Células-Tronco , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/terapia , Linfoma de Células B/genética , Linfoma de Células B/mortalidade , Linfoma de Células B/terapia , Masculino , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/mortalidade , Neoplasias do Mediastino/terapia , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Burkitt's lymphoma (BL) can often be cured by intensive chemotherapy, but the toxicity of such therapy precludes its use in the elderly and in patients with endemic BL in developing countries, necessitating new strategies. The normal germinal centre B cell is the presumed cell of origin for both BL and diffuse large B-cell lymphoma (DLBCL), yet gene expression analysis suggests that these malignancies may use different oncogenic pathways. BL is subdivided into a sporadic subtype that is diagnosed in developed countries, the Epstein-Barr-virus-associated endemic subtype, and an HIV-associated subtype, but it is unclear whether these subtypes use similar or divergent oncogenic mechanisms. Here we used high-throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways in BL that cooperate with MYC, the defining oncogene of this cancer. In 70% of sporadic BL cases, mutations affecting the transcription factor TCF3 (E2A) or its negative regulator ID3 fostered TCF3 dependency. TCF3 activated the pro-survival phosphatidylinositol-3-OH kinase pathway in BL, in part by augmenting tonic B-cell receptor signalling. In 38% of sporadic BL cases, oncogenic CCND3 mutations produced highly stable cyclin D3 isoforms that drive cell cycle progression. These findings suggest opportunities to improve therapy for patients with BL.
Assuntos
Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/genética , Genômica , Terapia de Alvo Molecular , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patologia , Ciclo Celular , Ciclina D3/genética , Ciclina D3/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Genes myc/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteínas Inibidoras de Diferenciação/genética , Proteínas Inibidoras de Diferenciação/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Interferência de RNA , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de SinaisRESUMO
Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma (PTCL) with a poor prognosis. We performed targeted resequencing on 92 cases of PTCL and identified frequent mutations affecting RHOA, TET2, DNMT3A, and isocitrate dehydrogenase 2 (IDH2). Although IDH2 mutations are largely confined to AITL, mutations of the other 3 can be found in other types of PTCL, although at lower frequencies. These findings indicate a key role of epigenetic regulation in the pathogenesis of AITL. However, the epigenetic alterations induced by these mutations and their role in AITL pathogenesis are still largely unknown. We correlated mutational status with gene expression and global DNA methylation changes in AITL. Strikingly, AITL cases with IDH2(R172) mutations demonstrated a distinct gene expression signature characterized by downregulation of genes associated with TH1 differentiation (eg, STAT1 and IFNG) and a striking enrichment of an interleukin 12-induced gene signature. Ectopic expression of IDH2(R172K) in the Jurkat cell line and CD4(+) T cells led to markedly increased levels of 2-hydroxyglutarate, histone-3 lysine methylation, and 5-methylcytosine and a decrease of 5-hydroxymethylcytosine. Correspondingly, clinical samples with IDH2 mutations displayed a prominent increase in H3K27me3 and DNA hypermethylation of gene promoters. Integrative analysis of gene expression and promoter methylation revealed recurrently hypermethylated genes involved in T-cell receptor signaling and T-cell differentiation that likely contribute to lymphomagenesis in AITL.