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1.
Zhonghua Bing Li Xue Za Zhi ; 48(5): 364-368, 2019 May 08.
Artigo em Chinês | MEDLINE | ID: mdl-31104675

RESUMO

Objective: To investigate the clinical presentation pathological diagnostic features and molecular genetics of paediatric-type follicular lymphoma (PTFL). Methods: Eight cases of PTFL at Fujian Cancer Hospital between January 2003 and May 2018 were analyzed by hematoxylin-eosin stain, immunohistochemistry, polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH). The relevant literature review was performed. Results: All patients were male with age ranging from 12 to 27 years (median age of 18 years and average age of 19 years). Clinical manifestations included painless lymph adenopathy, primarily involving head and neck lymph nodes (6/8). According to Ann Arbor stage, there were 7 patients at stage Ⅰ A and 1 patient at stage Ⅱ A. Histologically, the structure of the lymph nodes was effaced with pushing borders visible at the tumor periphery. The lesions consisted of expanding, irregular follicles that were arranged in back to back fashion along with thinning or disappearing sleeves. The starry sky phenomenon in the follicle was prominent with loss of polarity. Under high power magnification, the follicles were composed of uniform, medium-sized blastic cells in 5 cases or centroblast in 3 cases. The neoplastic cells were positive for B cell markers and germinal center markers primarily confined to the germinal center. Bcl-2 was negative in 7 cases and 1 case showed weak bcl-2 staining. MUM1 was negative in all cases. Ki-67 demonstrated a high proliferation index of great than 70% in 7 of 8 cases. Eight cases showed Ig clonal rearrangement. No bcl-2, bcl-6, and IRF4/MUM1 gene rearrangements by FISH were detected in all cases. One patient was treated with 6 cycles of CHOP after surgical resection. Other patients underwent only simple surgical resection. All patients were alive upon clinical follow-up. Conclusion: PTFL is a rare subtype of B cell lymphoma with unique clinical and pathological features. It should be distinguished from reactive follicular hyperplasia, nodal marginal lymphoma in children, large B-cell lymphoma with IRF4 rearrangement and usual follicular lymphoma.


Assuntos
Linfoma de Células B , Linfoma Folicular , Adolescente , Adulto , Criança , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma Folicular/diagnóstico , Linfoma Folicular/genética , Linfoma Folicular/patologia , Masculino , Proteínas Proto-Oncogênicas c-bcl-6 , Adulto Jovem
2.
PLoS One ; 14(2): e0212813, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30802265

RESUMO

Follicular lymphoma (FL) is an indolent but largely incurable disease. Some patients suffer histological transformation to a more aggressive subtype with poorer prognosis. This study aimed to improve our understanding of the genetics underlying FL histological transformation, and to identify genetic drivers or promoters of the transformation by elucidating the differences between FL samples from patients who did and did not transform. We conducted targeted massive parallel sequencing of 22 pre-transformed FL/transformed diffuse large B-cell lymphoma pairs and 20 diagnostic samples from non-transformed FL patients. Additionally, 22 matched samples from 11 transformed FL patients (pre-transformed FL and diffuse large B-cell lymphoma) and 9 non-transformed FLs were studied for copy number variation using SNP arrays. We identified recurrently mutated genes that were enriched at transformation, most notably LRP1B, GNA13 and POU2AF1, which have roles in B-cell differentiation, GC architecture and migration. Mutations in POU2AF1 might be associated with lower levels of expression, were more frequent in transformed FLs, and seemed to be specific to transformed- compared with de novo-diffuse large B-cell lymphomas. Pre-transformed FLs carried more mutations per sample and had greater subclonal heterogeneity than non-transformed FLs. Finally, we identified four mutated genes in FL samples that differed between patients who did and did not transform: NOTCH2, DTX1, UBE2A and HIST1H1E. The presence of mutations in these genes was associated with shorter time to transformation when mutated in the FL biopsies. This information might be useful for identifying patients at higher risk of transformation.


Assuntos
Linfócitos B , Transformação Celular Neoplásica , Linfoma Folicular , Linfoma Difuso de Grandes Células B , Mutação , Proteínas de Neoplasias , Adulto , Idoso , Linfócitos B/metabolismo , Linfócitos B/patologia , Biópsia , Diferenciação Celular/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Feminino , Seguimentos , Humanos , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo
3.
Zhonghua Bing Li Xue Za Zhi ; 48(2): 132-136, 2019 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-30695866

RESUMO

Objective: To investigate the clinicopathologic features of follicular lymphoma (FL) in children. Methods: One female and one male patients with FL diagnosed in the First College of Clinical Medical Science, China Three Gorges University and Beijing Friendship Hospital of the Capital University of Medical Science in February 2016 and June 2015 were studied by HE immunohistochemistry, EBER in situ hybridization, IgH and IgK gene rearrangement analysis and IRF4 fusion gene detection. Results: The two patients' age were 6.3 and 12 years, respectively. The lesions involved head and neck lymph nodes with duration of more than 2 months. Histopathologically, the lesions consisted of nodular proliferation of lymphoid follicles with diffuse distribution of large cells. Starry sky phenomenon was seen in one of the two cases. Immunohistochemistry showed that one case was positive for bcl-2 and MUM1, but negative for bcl-6 and CD10. Ki-67 index was>50% and oligoclonal IgK rearrangement was observed. The second case showed positivity for bcl-6, and CD10 but negative for bcl-2. Ki-67 index was>50% and clonal IgH FR1-JH and IgH FR2-JH rearrangements were detected. Both cases showed no evidence of IRF4 gene fusion. Conclusions: Childhood FL is a rare B-cell lymphoma with characteristic features and high-grade histomorphology. However, its immunophenotype and molecular genetic characteristics are divergent.


Assuntos
Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma Folicular/genética , Linfoma Folicular/patologia , Criança , China , Feminino , Rearranjo Gênico , Humanos , Imunoglobulinas/genética , Imuno-Histoquímica , Imunofenotipagem , Hibridização in Situ Fluorescente , Fatores Reguladores de Interferon/análise , Antígeno Ki-67/análise , Linfoma de Células B/química , Linfoma Folicular/química , Masculino , Neprilisina/análise , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-6/análise
5.
Blood ; 133(1): 81-93, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30446494

RESUMO

Although recent advances in molecular genetics have enabled improved risk classification of follicular lymphoma (FL) using, for example, the m7-FLIPI score, the impact on treatment has been limited. We aimed to assess the prognostic significance of copy-number aberrations (CNAs) and copy-neutral loss of heterozygosity (cnLOH) identified by chromosome genomic-array testing (CGAT) at FL diagnosis using prospectively collected clinical trial specimens from 255 patients enrolled in the SWOG study S0016. The impact of genomic aberrations was assessed for early progression (progressed or died within 2 years after registration), progression-free survival (PFS), and overall survival (OS). We showed that increased genomic complexity (ie, the total number of aberration calls) was associated with poor outcome in FL. Certain chromosome arms were critical for clinical outcome. Prognostic CNAs/cnLOH were identified: whereas early progression was correlated with 2p gain (P = .007; odds ratio [OR] = 2.55 [1.29, 5.03]) and 2p cnLOH (P = .005; OR = 10.9 [2.08, 57.2]), 2p gain specifically encompassing VRK2 and FANCL predicted PFS (P = .01; hazard ratio = 1.80 [1.14, 2.68]) as well as OS (P = .005; 2.40 [1.30, 4.40]); CDKN2A/B (9p) deletion correlated with worse PFS (P = .004, 3.50 [1.51, 8.28]); whereas CREBBP (16p) (P < .001; 6.70 [2.52, 17.58]) and TP53 (17p) (P < .001; 3.90 [1.85, 8.31]) deletion predicted worse OS. An independent cohort from the m7-FLIPI study was explored, and the prognostic significance of aberration count, and TP53 and CDKN2A/B deletion were further validated. In conclusion, assessing genomic aberrations at FL diagnosis with CGAT improves risk stratification independent of known clinical parameters, and provides a framework for development of future rational targeted therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Aberrações Cromossômicas , Genômica/métodos , Perda de Heterozigosidade , Linfoma Folicular/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Adulto Jovem
6.
Cancer Sci ; 110(1): 443-457, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30417470

RESUMO

Despite receiving rituximab-combined chemotherapy, follicular lymphoma (FL) patients often suffer tumor recurrence and understand that the cause of relapse in FL would thus significantly ameliorate the tumor therapeutics. In the present study, we show that TRA-1-60-expressing cells are a unique population in FL, converge to the conventional stem cell marker Oct3/4 and ALDH1-positive population, and resist current B-lymphoma agents. TRA-1-60 expression was observed in scattered lymphoma cells in FL tissues only as well as in resting B-lymphocytes inside germinal centers. Retrospective comparison between recurrent and cognate primary tissues showed that the number of TRA-1-60-positive cells from rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP)-treated FL had increased relative to primary tissue, a finding corroborated by assays on different rituximab-treated FL cell lines, FL-18 and DOHH2, wherein TRA-positive cell numbers increased over 10-fold compared to the untreated sample. Concordantly, scanty TRA-1-60-positive FL-18 cells implanted s.c. into mice evinced potent tumor-initiating capacity in vivo, where tumors were 12-fold larger in volume (P = 0.0021 < 0.005) and 13-fold heavier in weight (P = 0.0015 < 0.005) compared to those xenografted from TRA-negative cells. To explain these results, gene expression profiling and qPCR analysis indicated that TRA-1-60-positive cells defined a distinct population from that of TRA-negative cells, with upregulation of multiple drug transporters and therapeutic resistance genes. Hence, TRA-1-60-expressing cells in FL are considered to be vigorously intractable against conventional therapeutic agents, which may explain its refractory recurrence.


Assuntos
Antígenos de Superfície/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfoma Folicular/tratamento farmacológico , Proteoglicanas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Heterólogo , Carga Tumoral
7.
Hum Pathol ; 85: 112-118, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30448222

RESUMO

Immunohistochemistry is not only the most important tool for pathologists to establish a final diagnosis, but it can also inform decisions regarding optimal treatment methods. However, there is no universal standard notation for expressing immunohistochemical findings. For a diagnosis of malignant lymphoma, it is important to confirm the presence or absence of MYC translocation and communicate these results to a clinical audience. However, the criteria for selecting cases for fluorescence in situ hybridization (FISH) analysis to confirm MYC translocation are ill defined. We therefore devised a notation that we termed proportion of immunoreactivity/expression for immunohistochemistry (PRIME notation) based on the cellular proportion showing different antigen-antibody reactivity in immunohistochemistry (CPAR) and used it to examine the relationship between MYC translocation and the proportion of c-MYC+ lymphoma cells. We reviewed 82 cases diagnosed as diffuse large B-cell lymphoma or diffuse large B-cell lymphoma coexisting with grade 3A to 3B follicular lymphoma. The most common notation was "+/(weak)+/-" (49/82 cases [59.8%]); cases that were CPAR positive, weakly positive, and negative for tumor cells each accounted for about one-third of the total. Unexpectedly, no MYC translocation was observed by FISH in this group. Thus, FISH is not needed even if more than half of cells are c-MYC positive by PRIME notation. This is the first report describing a correspondence between immunohistochemical findings and chromosomal abnormality, reflecting findings at the protein and gene levels, respectively.


Assuntos
Rearranjo Gênico , Linfoma Folicular/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Biomarcadores Tumorais/metabolismo , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfoma Folicular/genética , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-myc/genética
9.
Br J Haematol ; 184(3): 373-383, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30565652

RESUMO

Long non-coding RNAs (lncRNAs) comprise a family of non-coding transcripts that are emerging as relevant gene expression regulators of different processes, including tumour development. To determine the possible contribution of lncRNA to the pathogenesis of follicular lymphoma (FL) we performed RNA-sequencing at high depth sequencing in primary FL samples ranging from grade 1-3A to aggressive grade 3B variants using unpurified (n = 16) and purified (n = 12) tumour cell suspensions from nodal samples. FL grade 3B had a significantly higher number of differentially expressed lncRNAs (dif-lncRNAs) with potential target coding genes related to cell cycle regulation. Nine out of the 18 selected dif-lncRNAs were validated by quantitative real time polymerase chain reaction in an independent series (n = 43) of FL. RP4-694A7.2 was identified as the top deregulated lncRNA potentially involved in cell proliferation. RP4-694A7.2 silencing in the WSU-FSCCL FL cell line reduced cell proliferation due to a block in the G1/S phase. The relationship between RP4-694A7.2 and proliferation was confirmed in primary samples as its expression levels positively related to the Ki-67 proliferation index. In summary, lncRNAs are differentially expressed across the clinico-biological spectrum of FL and a subset of them, related to cell cycle, may participate in cell proliferation regulation in these tumours.


Assuntos
Pontos de Checagem da Fase G1 do Ciclo Celular , Regulação Neoplásica da Expressão Gênica , Linfoma Folicular/metabolismo , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Pontos de Checagem da Fase S do Ciclo Celular , Feminino , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patologia , Masculino , RNA Longo não Codificante/genética , RNA Neoplásico/genética
10.
Arch Pathol Lab Med ; 143(1): 105-111, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29979613

RESUMO

CONTEXT.­: B-cell lymphomas exhibit balanced translocations that involve immunoglobulin loci and result from aberrant V(D)J recombination, class switch recombination, or somatic hypermutation. Although most of the breakpoints in the immunoglobulin loci occur in defined regions, those in the partner genes vary; therefore, it is unlikely that 2 independent clones would share identical breakpoints in both partners. Establishing whether a new lesion in a patient with history of lymphoma represents recurrence or a new process can be relevant. Polymerase chain reaction (PCR)-based clonality assays used in this setting rely only on evaluating the length of a given rearrangement. In contrast, next-generation sequencing (NGS) provides the exact translocation breakpoint at single-base resolution. OBJECTIVE.­: To determine if translocation breakpoint coordinates can serve as a molecular fingerprint unique to a distinct clonal population. DESIGN.­: Thirty-eight follicular lymphoma/diffuse large B-cell lymphoma samples collected from different anatomic sites and/or at different time points from 18 patients were analyzed by NGS. For comparison, PCR-based B-cell clonality and fluorescence in situ hybridization studies were performed on a subset of cases. RESULTS.­: IGH-BCL2 rearrangements were detected in all samples. The breakpoint coordinates on derivative chromosome(s) were identical in all samples from a given patient, but distinct between samples derived from different patients. Additionally, 5 patients carried a second rearrangement also with conserved breakpoint coordinates in the follow-up sample(s). CONCLUSIONS.­: Breakpoint coordinates in the immunoglobulin and partner genes can be used to establish clonal relatedness of anatomically/temporally distinct lesions. Additionally, an NGS-based approach has the potential to detect secondary translocations that may have prognostic and therapeutic significance.


Assuntos
Impressões Digitais de DNA , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Linfoma Folicular/genética , Linfoma Difuso de Grandes Células B/genética , Rearranjo Gênico , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Hibridização in Situ Fluorescente , Proteínas Proto-Oncogênicas c-bcl-2/genética , Translocação Genética
11.
Blood ; 133(10): 1119-1129, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30591526

RESUMO

Follicular lymphoma (FL) is a low-grade B-cell malignancy that transforms into a highly aggressive and lethal disease at a rate of 2% per year. Perfect isolation of the malignant B-cell population from a surgical biopsy is a significant challenge, masking important FL biology, such as immune checkpoint coexpression patterns. To resolve the underlying transcriptional networks of follicular B-cell lymphomas, we analyzed the transcriptomes of 34 188 cells derived from 6 primary FL tumors. For each tumor, we identified normal immune subpopulations and malignant B cells, based on gene expression. We used multicolor flow cytometry analysis of the same tumors to confirm our assignments of cellular lineages and validate our predictions of expressed proteins. Comparison of gene expression between matched malignant and normal B cells from the same patient revealed tumor-specific features. Malignant B cells exhibited restricted immunoglobulin (Ig) light chain expression (either Igκ or Igλ), as well the expected upregulation of the BCL2 gene, but also downregulation of the FCER2, CD52, and major histocompatibility complex class II genes. By analyzing thousands of individual cells per patient tumor, we identified the mosaic of malignant B-cell subclones that coexist within a FL and examined the characteristics of tumor-infiltrating T cells. We identified genes coexpressed with immune checkpoint molecules, such as CEBPA and B2M in regulatory T (Treg) cells, providing a better understanding of the gene networks involved in immune regulation. In summary, parallel measurement of single-cell expression in thousands of tumor cells and tumor-infiltrating lymphocytes can be used to obtain a systems-level view of the tumor microenvironment and identify new avenues for therapeutic development.


Assuntos
Linfoma de Células B/genética , Linfoma Folicular/genética , Linfócitos T Reguladores/citologia , Biópsia , Proteínas Estimuladoras de Ligação a CCAAT/genética , Linfócitos T CD4-Positivos/citologia , Antígeno CD52/genética , Linhagem da Célula , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Sistema Imunitário , Imunoglobulina G , Lectinas Tipo C/genética , Leucócitos Mononucleares/citologia , Linfoma de Células B/sangue , Linfoma Folicular/sangue , Tonsila Palatina/metabolismo , Receptores de IgE/genética , Análise de Sequência de RNA , Transcriptoma , Microambiente Tumoral , Microglobulina beta-2/genética
12.
Hematology Am Soc Hematol Educ Program ; 2018(1): 189-193, 2018 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-30504309

RESUMO

Follicular lymphoma (FL) is an incurable but treatable disease with vast treatment options. Despite the abundance of efficacious treatment modalities, there is no universally agreed upon standard approach to treatment, particularly in the relapsed/refractory setting. There is an increasing need for more robust and clinically available tools to risk-stratify patients and identify those likely to experience early relapse, which is currently recognized as the unmet need in FL. Additionally, the use of gene-expression profiling and next-generation sequencing techniques in recent years has led to a wealth of knowledge regarding the molecular drivers of lymphomagenesis. However, much of this knowledge is not currently available in the clinic to inform treatment decisions. Future studies are needed to generate clinically relevant predictive models adept at incorporating patient-specific and molecular features to inform management strategies along the entire disease continuum as treatment decisions should not be made in a vacuum with a one-size-fits-all approach. Sequencing of therapy in the management of relapsed FL should involve personalized decision-making for care plans that balance patient characteristics, preferences, and comorbidities with treatment-related factors such as efficacy, toxicity profile, and mechanisms of action to achieve a durable, quality remission.


Assuntos
Transformação Celular Neoplásica , Sequenciamento de Nucleotídeos em Larga Escala , Linfoma Folicular , Modelos Biológicos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Humanos , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Linfoma Folicular/terapia , Recidiva
13.
Pathol Int ; 68(12): 665-676, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30456840

RESUMO

The incidence of lymphoma has rapidly increased over the last 40 years in Japan, following a trend that is very similar to that of breast cancer. In particular, the relative frequency of follicular lymphoma (FL) has reached that in Western countries. Given its indolence, a "watch-and-wait" approach is often applied to FL patients. We have shown that FL is often detected in the second portion of the duodenum and has a distinct follicular dendritic cell distribution and heavy chain variable usage similar to mucosa-associated lymphoid tissue (MALT) lymphoma. Although the t(14;18)(q32;q21) frequency is the same as in the nodal subtype of FL, there are also ongoing mutations, immunopositivity for cluster of differentiation 10 and B-cell lymphoma (BCL)6, and overexpression of BCL2. Gene expression profiling has shown that it is more similar to gastric MALT lymphoma than to nodal FL. Duodenal-type FL lacks the activation-induced cytidine deaminase (AID) expression observed in nodal ones, although this may be compensated for by BTB domain and CNC homolog 2. Based on these findings, duodenal-type FL has been included in the Revised 4th edition of the World Health Organization classification published in late 2017.


Assuntos
Neoplasias Duodenais/patologia , Linfoma Folicular/patologia , Neoplasias Duodenais/classificação , Neoplasias Duodenais/genética , Humanos , Japão , Linfoma Folicular/classificação , Linfoma Folicular/genética
15.
Sci Rep ; 8(1): 16152, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30385851

RESUMO

The KIF14 locus is gained and overexpressed in various malignancies, with prognostic relevance. Its protein product, a mitotic kinesin, accelerates growth of normal mammary epithelial cells in vitro and retinoblastoma tumours in a mouse model, while KIF14 knockdown blocks growth of brain, liver, ovarian, breast, prostate, and other tumour cells and xenografts. However, the tumour-initiating effects of Kif14 overexpression have not been studied. We aged a cohort of Kif14-overexpressing transgenic mice and wild-type littermates and documented survival, cause of death, and tumour burden. The Kif14 transgene was expressed in all tissues examined, and was associated with increased proliferation marker expression. Neither mouse weights nor overall survival differed between genotypes. However, Kif14 transgenic mice showed a higher incidence of fatal lymphomas (73 vs. 50%, p = 0.03, Fisher's exact test), primarily follicular and diffuse B-cell lymphomas. Non-tumour findings included a bilateral ballooning degeneration of lens in 12% of Kif14 transgenic mice but no wild-type mice (p = 0.02). Overall, this work reveals a novel association of Kif14 overexpression with lymphoma but suggests that Kif14 does not have as prominent a role in initiating cancer in other cell types as it does in accelerating tumour development in response to other oncogenic insults.


Assuntos
Biomarcadores Tumorais/genética , Carcinogênese/genética , Cinesina/genética , Linfoma de Células B/genética , Linfoma Folicular/genética , Animais , Regulação Neoplásica da Expressão Gênica/genética , Genótipo , Humanos , Linfoma de Células B/patologia , Linfoma Folicular/patologia , Camundongos , Prognóstico , Carga Tumoral/genética
17.
Diagn Pathol ; 13(1): 78, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30322385

RESUMO

BACKGROUND: Transformation of follicular lymphoma most typically occurs as diffuse large B-cell lymphoma, however other forms of transformation such as classic Hodgkin lymphoma and lymphoblastic transformation can occur. Secondary malignant histiocytosis also represents a rare form of transformation, which is thought to occur due to a process of transdifferentiation whereby the lymphoma cells exhibit lineage plasticity and lose all evidence of B-cell phenotype and instead acquire the phenotype of a histiocytic neoplasm. Little is known about the underlying genetic alterations that occur during this unusual process. Comparative genetic analysis of pre- and post-transformation/transdifferentiation would be one tool by which we could better understand how this phenomenon occurs. CASE PRESENTATION: Here we report the clinical, immunophenotypic and genetic features of a rare case of secondary malignant histiocytosis, Langerhans cell-type (Langerhans cell sarcoma) arising from a previous low grade follicular lymphoma. FISH analysis confirmed the presence of IgH/BCL2 rearrangement in both the low grade follicular lymphoma (FL) and transformed Langerhans cells sarcoma (LCS) samples, demonstrating a clonal relationship. Comparative whole exome sequencing was then performed, which identified a KRAS p.G13D mutation in the LCS that was not present in the FL. CONCLUSIONS: This report highlights genetic alterations, in particular an acquired somatic KRAS mutation, that may occur during transdifferentiation, with additional significance of KRAS mutation as a possible therapeutic target in cases which otherwise would have limited treatment options.


Assuntos
Linfócitos B/patologia , Sarcoma Histiocítico/metabolismo , Células de Langerhans/patologia , Linfoma Folicular/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Sarcoma Histiocítico/patologia , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Imunofenotipagem/métodos , Hibridização in Situ Fluorescente/métodos , Sarcoma de Células de Langerhans/patologia , Linfoma Folicular/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
18.
Blood ; 132(22): 2389-2400, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30213873

RESUMO

Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma. Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying tFL are unclear. Here we performed the first profiling of expression of microRNAs (miRNAs) in paired samples of FL and tFL and identified 5 miRNAs as being differentially expressed. We focused on one of these miRNAs, namely miR-150, which was uniformly downmodulated in all examined tFLs (∼3.5-fold), and observed that high levels of MYC are responsible for repressing miR-150 in tFL by binding in its upstream region. This MYC-mediated repression of miR-150 in B cells is not dependent on LIN28A/B proteins, which influence the maturation of miR-150 precursor (pri-miR-150) in myeloid cells. We also demonstrated that low miR-150 levels in tFL lead to upregulation of its target, namely FOXP1 protein, which is a known positive regulator of cell survival, as well as B-cell receptor and NF-κB signaling in malignant B cells. We revealed that low levels of miR-150 and high levels of its target, FOXP1, are associated with shorter overall survival in FL and suggest that miR-150 could serve as a good biomarker measurable in formalin-fixed paraffin-embedded tissue. Overall, our study demonstrates the role of the MYC/miR-150/FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.


Assuntos
Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Linfoma Folicular/genética , MicroRNAs/genética , Proteínas Repressoras/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Regulação para Baixo , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-myc/genética , Ativação Transcricional , Regulação para Cima
19.
Wiad Lek ; 71(5): 1095-1098, 2018.
Artigo em Polonês | MEDLINE | ID: mdl-30176648

RESUMO

Follicular lymphoma (FL) is the most common of indolent non-Hodgkin's lymphomas. Its first-line treatment, based on immuno-chemotherapy with the anti-CD20 monoclonal antibody rituximab, is characterized by a high overall response rate to therapy. However, the disease is not curable in most cases and frequent relapses and transformations to other higher-grade lymphomas are observed. The effectiveness of the treatment of relapsed or refractory FL is not satisfactory, therefore the novel drugs are under investigation. Data from clinical trials with tazemetostat (an EZH2 inhibitor) in a group of patients with confirmed presence of the EZH2 mutation showed that this treatment may be an alternative to currently used chemotherapy regimens.


Assuntos
Benzamidas/uso terapêutico , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Linfoma Folicular/tratamento farmacológico , Piridonas/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patologia , Mutação , Recidiva , Resultado do Tratamento
20.
Curr Hematol Malig Rep ; 13(5): 369-382, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30112706

RESUMO

PURPOSE OF REVIEW: Enhancer of Zeste Homolog 2 (EZH2) is histone methyltransferase and catalyzes the methylation of histone 3 lysine 27, a mark of transcriptional repression. Various studies have elucidated the complex role of EZH2 in both normal biology and tumorigenesis. Here, we critically review the emerging role of EZH2 in malignancies, the development of small molecule inhibitors of EZH2, and their application in lymphoma. RECENT FINDINGS: Activating mutations and overexpression of EZH2 are found in non-Hodgkin lymphoma (NHL). As a result, several EZH2 inhibitors have been developed and entered clinical investigation. Tazemetostat, first-in-class EZH2 inhibitor, demonstrated enhanced clinical activity in mutant follicular lymphoma and diffuse large B cell lymphoma. With the early activity noted by tazemetostat in B cell lymphomas, the role of EZH2 inhibition in NHL is becoming more evident. This can be leveraged in future rationale combinations to enhance the activity of EZH2 inhibitors.


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Proteína Potenciadora do Homólogo 2 de Zeste , Inibidores Enzimáticos/uso terapêutico , Linfoma Folicular , Linfoma Difuso de Grandes Células B , Proteínas de Neoplasias , Piridonas/uso terapêutico , Animais , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Humanos , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/enzimologia , Linfoma Folicular/genética , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/enzimologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo
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