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1.
Blood ; 141(12): 1425-1441, 2023 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-36179280

RESUMO

Upregulation of the proto-oncogene T-cell leukemia/lymphoma 1A (TCL1A) is causally implicated in various B-cell and T-cell malignancies. High-level TCL1A correlates with aggressive disease features and inferior clinical outcomes. However, the molecular and cell biological consequences of, particularly nuclear, TCL1A are not fully elucidated. We observed here in mouse models of subcellular site-specific TCL1A-induced lymphomagenesis that TCL1A exerts a strong transforming impact via nuclear topography. In proteomic screens of TCL1A-bound molecules in chronic lymphocytic leukemia (CLL) cells and B-cell lymphoma lines, we identified regulators of cell cycle and DNA repair pathways as novel TCL1A interactors, particularly enriched under induced DNA damage and mitosis. By functional mapping and in silico modeling, we specifically identified the mitotic checkpoint protein, cell division cycle 20 (CDC20), as a direct TCL1A interactor. According to the regulatory impact of TCL1A on the activity of the CDC20-containing mitotic checkpoint and anaphase-promoting complexes during mitotic progression, TCL1A overexpression accelerated cell cycle transition in B-cell lymphoma lines, impaired apoptotic damage responses in association with pronounced chromosome missegregation, and caused cellular aneuploidy in Eµ-TCL1A mice. Among hematopoietic cancers, CDC20 levels seem particularly low in CLL. CDC20 expression negatively correlated with TCL1A and lower expression marked more aggressive and genomically instable disease and cellular phenotypes. Knockdown of Cdc20 in TCL1A-initiated murine CLL promoted aneuploidy and leukemic acceleration. Taken together, we discovered a novel cell cycle-associated effect of TCL1A abrogating controlled cell cycle transition. This adds to our concept of oncogenic TCL1A by targeting genome stability. Overall, we propose that TCL1A acts as a pleiotropic adapter molecule with a synergistic net effect of multiple hijacked pathways.


Assuntos
Leucemia Linfocítica Crônica de Células B , Linfoma de Células B , Camundongos , Animais , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteômica , Linfoma de Células B/genética , Ciclo Celular/genética , Proto-Oncogenes , Proteínas de Ciclo Celular/genética , Mitose
3.
Oncotarget ; 9(22): 15942-15951, 2018 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-29662618

RESUMO

The mechanisms involved in malignant transformation of mature B and T lymphocytes are still poorly understood. In a previous study, we compared gene expression profiles of the tumor cells of Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) to their normal cellular counterparts and found the basic leucine zipper protein ATF-like 3 (BATF3) to be significantly upregulated in the tumor cells of both entities. To assess the oncogenic potential of BATF3 in lymphomagenesis and to dissect the molecular interactions of BATF3 in lymphoma cells, we retrovirally transduced murine mature T and B cells with a BATF3-encoding viral vector and transplanted each population into Rag1-deficient recipients. Intriguingly, BATF3-expressing B lymphocytes readily induced B-cell lymphomas after characteristic latencies, whereas T-cell transplanted animals remained healthy throughout the observation time. Further analyses revealed a germinal center B-cell-like phenotype of most BATF3-initiated lymphomas. In a multiple myeloma cell line, BATF3 inhibited BLIMP1 expression, potentially illuminating an oncogenic action of BATF3 in B-cell lymphomagenesis. In conclusion, BATF3 overexpression induces malignant transformation of mature B cells and might serve as a potential target in B-cell lymphoma treatment.

4.
Oncotarget ; 9(16): 12971-12981, 2018 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-29560124

RESUMO

Classical Hodgkin lymphoma (cHL) is a hematopoietic malignancy with a characteristic cellular composition. The tumor mass is made up of infiltrated lymphocytes and other cells of hematologic origin but only very few neoplastic cells that are mainly identified by the diagnostic marker CD30. While most patients with early stage cHL can be cured by standard therapy, treatment options for relapsed or refractory cHL are still not sufficient, although immunotherapy-based approaches for the treatment of cHL patients have gained ground in the last decade. Here, we suggest a novel therapeutic concept based on oncolytic viruses selectively destroying the CD30+-positive cHL tumor cells. Relying on a recently described CD30-specific scFv we have generated CD30-targeted measles virus (MV-CD30) and vesicular stomatitis virus (VSV-CD30). For VSV-CD30 the VSV glycoprotein G reading frame was replaced by those of the CD30-targeted MV glycoproteins. Both viruses were found to be highly selective for CD30-positive cells as demonstrated by infection of co-cultures of target and non-target cells as well as through blocking infection by soluble CD30. Notably, VSV-CD30 yielded much higher titers than MV-CD30 and resulted in a more rapid and efficient killing of cultivated cHL-derived cell lines. Mouse tumor models revealed that intratumorally, as well as systemically injected VSV-CD30, infected cHL xenografts and significantly slowed down tumor growth resulting in a substantially prolonged survival of tumor-bearing mice. Taken together, the data support further preclinical testing of VSV-CD30 as novel therapeutic agent for the treatment of cHL and other CD30+-positive malignancies.

5.
PLoS One ; 12(5): e0177378, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28505189

RESUMO

The hallmark of classical Hodgkin lymphoma (cHL) is the presence of giant, mostly multinucleated Hodgkin-Reed-Sternberg (HRS) cells. Whereas it has recently been shown that giant HRS cells evolve from small Hodgkin cells by incomplete cytokinesis and re-fusion of tethered sister cells, it remains unsolved why this phenomenon particularly takes place in this lymphoma and what the differences between these cell types of variable sizes are. The aim of the present study was to characterize microdissected small and giant HRS cells by gene expression profiling and to assess differences of clonal growth behavior as well as susceptibility toward cytotoxic intervention between these different cell types to provide more insight into their distinct cellular potential. Applying stringent filter criteria, only two differentially expressed genes between small and giant HRS cells, SHFM1 and LDHB, were identified. With looser filter criteria, 13 genes were identified to be differentially overexpressed in small compared to giant HRS cells. These were mainly related to energy metabolism and protein synthesis, further suggesting that small Hodgkin cells resemble the proliferative compartment of cHL. SHFM1, which is known to be involved in the generation of giant cells, was downregulated in giant RS cells at the RNA level. However, reduced mRNA levels of SHFM1, LDHB and HSPA8 did not translate into decreased protein levels in giant HRS cells. In cell culture experiments it was observed that the fraction of small and big HRS cells was adjusted to the basic level several days after enrichment of these populations via cell sorting, indicating that small and big HRS cells can reconstitute the full spectrum of cells usually observed in the culture. However, assessment of clonal growth of HRS cells indicated a significantly reduced potential of big HRS cells to form single cell colonies. Taken together, our findings pinpoint to strong similarities but also some differences between small and big HRS cells.


Assuntos
Perfilação da Expressão Gênica , Doença de Hodgkin/genética , Doença de Hodgkin/patologia , Células de Reed-Sternberg/metabolismo , Células de Reed-Sternberg/patologia , Transcriptoma , Antineoplásicos/uso terapêutico , Biomarcadores , Brentuximab Vedotin , Linhagem Celular Tumoral , Tamanho Celular , Análise por Conglomerados , Regulação Neoplásica da Expressão Gênica , Doença de Hodgkin/tratamento farmacológico , Humanos , Imunoconjugados/uso terapêutico , Imuno-Histoquímica , Imunofenotipagem
6.
Leuk Lymphoma ; 58(4): 788-796, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27643643

RESUMO

Growing attention in mature T-cell lymphomas/leukemias (MTCL) is committed to more accurate and meaningful classifications, improved pathogenetic concepts and expanded therapeutic options. This requires considerations of the immunologic concepts of T-cell homeostasis and the specifics of T-cell receptor (TCR) affinities and signaling. Scientists from various disciplines established the CONTROL-T research unit and in an international conference on MTCL they brought together experts from T-cell immunity, oncology, immunotherapy and systems biology. We report here meeting highlights on the covered topics of diagnostic pitfalls, implications by the new WHO classification, insights from discovered genomic lesions as well as TCR-centric concepts of cellular dynamics in host defense, auto-immunity and tumorigenic clonal escape, including predictions to be derived from in vivo imaging and mathematical modeling. Presentations on novel treatment approaches were supplemented by strategies of optimizing T-cell immunotherapies. Work packages, that in joint efforts would advance the field of MTCL more efficiently, are identified.


Assuntos
Linfoma de Células T/diagnóstico , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Gerenciamento Clínico , Humanos , Imunoterapia , Linfoma de Células T/etiologia , Linfoma de Células T/patologia , Linfoma de Células T/terapia , Gradação de Tumores , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Organização Mundial da Saúde
7.
Oncotarget ; 7(44): 72197-72210, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27708232

RESUMO

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an indolent lymphoma, but can transform into diffuse large B cell lymphoma (DLBCL), showing a more aggressive clinical behavior. Little is known about these cases on the molecular level. Therefore, the aim of the present study was to characterize DLBCL transformed from NLPHL (LP-DLBCL) by gene expression profiling (GEP). GEP revealed an inflammatory signature pinpointing to a specific host response. In a coculture model resembling this host response, DEV tumor cells showed an impaired growth behavior. Mechanisms involved in the reduced tumor cell proliferation included a downregulation of MYC and its target genes. Lack of MYC expression was also confirmed in 12/16 LP-DLBCL by immunohistochemistry. Furthermore, CD274/PD-L1 was upregulated in DEV tumor cells after coculture with T cells or monocytes and its expression was validated in 12/19 cases of LP-DLBCL. Thereby, our data provide new insights into the pathogenesis of LP-DLBCL and an explanation for the relatively low tumor cell content. Moreover, the findings suggest that treatment of these patients with immune checkpoint inhibitors may enhance an already ongoing host response in these patients.


Assuntos
Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Doença de Hodgkin/genética , Inflamação/patologia , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Adulto , Idoso , Antígeno B7-H1/metabolismo , Biópsia , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/patologia , Técnicas de Cocultura , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Doença de Hodgkin/patologia , Humanos , Imuno-Histoquímica , Linfonodos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Monócitos , Regulação para Cima
8.
Oncotarget ; 7(29): 46579-46588, 2016 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-27366944

RESUMO

As current classical Hodgkin lymphoma (cHL) treatment strategies have pronounced side-effects, specific inhibition of signaling pathways may offer novel strategies in cHL therapy. Basal autophagy, a regulated catabolic pathway to degrade cell's own components, is in cancer linked with both, tumor suppression or promotion. The finding that basal autophagy enhances tumor cell survival would thus lead to immediately testable strategies for novel therapies. Thus, we studied its contribution in cHL.We found constitutive activation of autophagy in cHL cell lines and primary tissue. The expression of key autophagy-relevant proteins (e.g. Beclin-1, ULK1) and LC3 processing was increased in cHL cells, even in lymphoma cases. Consistently, cHL cells exhibited elevated numbers of autophagic vacuoles and intact autophagic flux. Autophagy inhibition with chloroquine or inactivation of ATG5 induced apoptosis and reduced proliferation of cHL cells. Chloroquine-mediated inhibition of basal autophagy significantly impaired HL growth in-vivo in NOD SCID γc-/- (NSG) mice. We found that basal autophagy plays a pivotal role in sustaining mitochondrial function.We conclude that cHL cells require basal autophagy for growth, survival and sustained metabolism making them sensitive to autophagy inhibition. This suggests basal autophagy as useful target for new strategies in cHL treatment.


Assuntos
Autofagia/fisiologia , Doença de Hodgkin/tratamento farmacológico , Células de Reed-Sternberg/fisiologia , Animais , Autofagia/efeitos dos fármacos , Proteína 5 Relacionada à Autofagia/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Cloroquina/farmacologia , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Camundongos , Camundongos SCID , Mitocôndrias/metabolismo , Fosforilação Oxidativa
9.
Oncoimmunology ; 5(6): e1160186, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27471632

RESUMO

Hodgkin lymphoma (HL) presents with a unique histologic pattern. Pathognomonic Hodgkin and Reed-Sternberg (HRS) cells usually account for less than 1% of the tumor and are embedded in a reactive infiltrate mainly comprised of CD4(+) T cells. HRS cells induce an immunosuppressive microenvironment and thereby escape antitumor immunity. To investigate the impact of interactions between HRS cells and T cells, we performed long-term co-culture studies that were further translated into a xenograft model. Surprisingly, we revealed a strong antitumor potential of allogeneic CD4(+) T cells against HL cell lines. HRS and CD4(+) T cells interact by adhesion complexes similar to immunological synapses. Tumor-cell killing was likely based on the recognition of allogeneic major histocompatibility complex class II (MHC-II) receptor, while CD4(+) T cells from MHC-II compatible donors did not develop any antitumor potential in case of HL cell line L428. However, gene expression profiling (GEP) of co-cultured HRS cells as well as tumor infiltration of matched CD4(+) T cells indicated cellular interactions. Moreover, matched CD4(+) T cells could be activated to kill CD30(+) HRS cells when redirected with a CD30-specific chimeric antigen receptor. Our work gives novel insights into the crosstalk between HRS and CD4(+) T cells, suggesting the latter as potent effector cells in the adoptive cell therapy of HL.

10.
Commun Integr Biol ; 7: e28602, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25346790

RESUMO

Multinucleated giant tumor cells are frequently observed in tissue sections of lymphoma patients. In Hodgkin lymphoma (HL), these cells are pathognomonic for the disease and named Reed-Sternberg (RS) cells. Despite the well-described disease-promoting functions of RS cells, their development has remained obscure. We addressed this open question by continuous live cell imaging to observe the generation of RS cells. Single-cell tracking of HL cell lines revealed that RS cells develop from mononucleated progenitors that divide and subsequently re-fuse, before they grow and become multinucleated giant cells. Thus, RS cell generation is neither due to cell fusion of unrelated Hodgkin cells nor to endomitosis, as previously suggested. In the majority of cases, re-fusion of daughter cells was preceded by an incomplete cytokinesis, visualized by a persistent microtubule bridge connecting the cells. This surprising finding describes a novel mechanism for the formation of multinuclear giant cells with potential relevance beyond HL.

11.
Mod Pathol ; 27(10): 1345-54, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24633193

RESUMO

Classical Hodgkin lymphoma and ALK(-) anaplastic large cell lymphoma share many features like strong CD30 expression and usually loss of B- and T-cell markers. However, their clinical course is dramatically different with curability rates of >90% for classical Hodgkin lymphoma and an unfavorable prognosis for anaplastic large cell lymphoma. Classical Hodgkin lymphoma and ALK(-) anaplastic large cell lymphoma can usually be distinguished by PAX5 expression in the Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma and expression of cytotoxic molecules in tumor cells of anaplastic large cell lymphoma. However, in some cases the differential diagnosis is difficult owing to absence of established markers. To be able to better classify these cases, we reevaluated gene expression data of microdissected tumor cells of both lymphomas for differentially expressed genes. A classifier was established, comprising four genes strongly expressed in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma (MDC/CCL22, CD83, STAT3, and TUBB2B). Applying this classifier to a test cohort, Hodgkin lymphoma was successfully distinguished from ALK(-) anaplastic large cell lymphoma with an accuracy of 97% (43/44). MDC/CCL22, CD83, and STAT3 have also been found to be expressed in antigen-presenting cells. Therefore, based on our established classifier, Hodgkin and Reed-Sternberg cells differ from tumor cells of anaplastic large cell lymphoma, which can successfully be applied for practical purposes in histopathologic diagnostics.


Assuntos
Biomarcadores Tumorais/análise , Doença de Hodgkin/classificação , Doença de Hodgkin/diagnóstico , Linfoma Anaplásico de Células Grandes/classificação , Linfoma Anaplásico de Células Grandes/diagnóstico , Adulto , Idoso , Antígenos CD , Quimiocina CCL22 , Análise por Conglomerados , Diagnóstico Diferencial , Feminino , Humanos , Imunoglobulinas , Imuno-Histoquímica , Masculino , Glicoproteínas de Membrana , Pessoa de Meia-Idade , Células de Reed-Sternberg/patologia , Fator de Transcrição STAT3 , Análise Serial de Tecidos , Transcriptoma , Tubulina (Proteína) , Antígeno CD83
12.
Proc Natl Acad Sci U S A ; 110(51): 20729-34, 2013 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-24302766

RESUMO

Multinucleated Reed-Sternberg (RS) cells are pathognomonic for classical Hodgkin lymphoma (HL), and their presence is essential for diagnosis. How these giant tumor cells develop is controversial, however. It has been postulated that RS cells arise from mononucleated Hodgkin cells via endomitosis. Conversely, continuous single-cell tracking of HL cell lines by long-term time-lapse microscopy has identified cell fusion as the main route of RS cell formation. In contrast to growth-induced formation of giant Hodgkin cells, fusion of small mononuclear cells followed by a size increase gives rise to giant RS cells. Of note, fusion of cells originating from the same ancestor, termed re-fusion, is seen nearly exclusively. In the majority of cases, re-fusion of daughter cells is preceded by incomplete cytokinesis, as demonstrated by microtubule bonds among the cells. We confirm at the level of individual tracked cells that giant Hodgkin and RS cells have little proliferative capacity, further supporting small mononuclear Hodgkin cells as the proliferative compartment of the HL tumor clone. In addition, sister cells show a shared propensity for re-fusion, providing evidence of early RS cell fate commitment. Thus, RS cell generation is related neither to cell fusion of unrelated Hodgkin cells nor to endomitosis, but rather is mediated by re-fusion of daughter cells that underwent mitosis. This surprising finding supports the existence of a unique mechanism for the generation of multinuclear RS cells that may have implications beyond HL, given that RS-like cells are frequently observed in several other lymphoproliferative diseases as well.


Assuntos
Citocinese , Células Gigantes , Doença de Hodgkin , Leucócitos Mononucleares , Células de Reed-Sternberg , Fusão Celular , Linhagem Celular Tumoral , Células Gigantes/metabolismo , Células Gigantes/patologia , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Células de Reed-Sternberg/metabolismo , Células de Reed-Sternberg/patologia
13.
PLoS One ; 8(12): e81675, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24349109

RESUMO

BACKGROUND: Cannabinoid receptor 1 (CB1) is expressed in certain types of malignancies. An analysis of CB1 expression and function in Hodgkin lymphoma (HL), one of the most frequent lymphomas, was not performed to date. DESIGN AND METHODS: We examined the distribution of CB1 protein in primary cases of HL. Using lymphoma derived cell lines, the role of CB1 signaling on cell survival was investigated. RESULTS: A predominant expression of CB1 was found in Hodgkin-Reed-Sternberg cells in a vast majority of classical HL cases. The HL cell lines L428, L540 and KM-H2 showed strong CB1-abundance and displayed a dose-dependent decline of viability under CB1 inhibition with AM251. Further, application of AM251 led to decrease of constitutively active NFκB/p65, a crucial survival factor of HRS-cells, and was followed by elevation of apoptotic markers in HL cells. CONCLUSIONS: The present study identifies CB1 as a feature of HL, which might serve as a potential selective target in the treatment of Hodgkin lymphoma.


Assuntos
Regulação Neoplásica da Expressão Gênica , Doença de Hodgkin/genética , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
14.
PLoS One ; 8(11): e78812, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24244368

RESUMO

In contrast to the commonly indolent clinical behavior of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), T cell/histiocyte rich large B cell lymphoma (THRLBCL) is frequently diagnosed in advanced clinical stages and has a poor prognosis. Besides the different clinical presentations of these lymphoma entities, there are variants of NLPHL with considerable histopathologic overlap compared to THRLBCL. Especially THRLBCL-like NLPHL, a diffuse form of NLPHL, often presents a histopathologic pattern similar to THRLBCL, suggesting a close relationship between both lymphoma entities. To corroborate this hypothesis, we performed gene expression profiling of microdissected tumor cells of NLPHL, THRLBCL-like NLPHL and THRLBCL. In unsupervised analyses, the lymphomas did not cluster according to their entity. Moreover, even in supervised analyses, very few consistently differentially expressed transcripts were found, and for these genes the extent of differential expression was only moderate. Hence, there are no clear and consistent differences in the gene expression of the tumor cells of NLPHL, THRLBCL-like NLPHL and THRLBCL. Based on the gene expression studies, we identified BAT3/BAG6, HIGD1A, and FAT10/UBD as immunohistochemical markers expressed in the tumor cells of all three lymphomas. Characterization of the tumor microenvironment for infiltrating T cells and histiocytes revealed significant differences in the cellular composition between typical NLPHL and THRLBCL cases. However, THRLBCL-like NLPHL presented a histopathologic pattern more related to THRLBCL than NLPHL. In conclusion, NLPHL and THRLBCL may represent a spectrum of the same disease. The different clinical behavior of these lymphomas may be strongly influenced by differences in the lymphoma microenvironment, possibly related to the immune status of the patient at the timepoint of diagnosis.


Assuntos
Regulação Neoplásica da Expressão Gênica , Doença de Hodgkin , Linfócitos , Linfoma Folicular , Linfoma Difuso de Grandes Células B , Linfoma de Células T , Proteínas de Neoplasias/biossíntese , Feminino , Perfilação da Expressão Gênica , Doença de Hodgkin/classificação , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Linfócitos/metabolismo , Linfócitos/patologia , Linfoma Folicular/classificação , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma de Células T/classificação , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Masculino
15.
Crit Rev Oncol Hematol ; 88(3): 680-95, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23972664

RESUMO

Mature T-cell lymphomas/leukemias (MTCL) have been understudied lymphoid neoplasms that currently receive growing attention. Our historically rudimentary molecular understanding and dissatisfactory interventional success in this complex and for the most part poor-prognostic group of tumors is only slightly improving. A major limiting aspect in further progress in these rare neoplasms is the lack of suitable model systems that would substantially facilitate pathogenic studies and pre-clinical drug evaluations. Such representations of MTCL have thus far not been systematically appraised. We therefore provide an overview on existing models and point out their particular advantages and limitations in the context of the specific scientific questions. After addressing issues of species-specific differences and classifications, we summarize data on MTCL cell lines of human as well as murine origin, on murine strain predispositions to MTCL, on available models of genetically engineered mice, and on transplant systems. From an in-silico meta-analysis of available primary data of gene expression profiles on human MTCL we cross-reference genes reported to transform T-cells in mice and reflect on their general vs entity-restricted relevance and on target-promoter influences. Overall, we identify the urgent need for new models of higher fidelity to human MTCL with respect to their increasingly recognized diversity and to predictions of drug response.


Assuntos
Linfoma de Células T/etiologia , Linfoma de Células T/patologia , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Modelos Animais de Doenças , Humanos , Camundongos , Gradação de Tumores
16.
Mol Ther ; 21(6): 1160-8, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23609016

RESUMO

Retroviral vectors (RVs) are powerful tools in clinical gene therapy. However, stable genomic integration of RVs can be oncogenic, as reported in several animal models and in clinical trials. Previously, we observed that T-cell receptor (TCR) polyclonal mature T cells are resistant to transformation after gammaretroviral transfer of (proto-)oncogenes, whereas TCR-oligoclonal T cells were transformable in the same setting. Here, we describe the induction of a mature T-cell lymphoma (MTCL) in TCR-oligoclonal OT-I transgenic T cells, transduced with an enhanced green fluorescent protein (EGFP)-encoding gammaretroviral vector. The tumor cells were of a mature T-cell phenotype and serially transplantable. Integration site analysis revealed a proviral hit in Janus kinase 1 (Jak1), which resulted in Jak1 overexpression and Jak/STAT-pathway activation, particularly via signal transducer and activator of transcription 3 (STAT3). Specific inhibition of Jak1 markedly delayed tumor growth. A systematic meta-analysis of available gene expression data on human mature T-cell lymphomas/leukemias confirmed the relevance of Jak/STAT overexpression in sporadic human T-cell tumorigenesis. To our knowledge, this is the first study to describe RV-associated insertional mutagenesis in mature T cells.


Assuntos
Linfoma de Células T/genética , Linfoma de Células T/terapia , Mutagênese Insercional/métodos , Retroviridae/genética , Linfócitos T/metabolismo , Animais , Linhagem Celular Tumoral , Éxons , Feminino , Vetores Genéticos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Linfoma de Células T/patologia , Camundongos , Fosforilação , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Transativadores/genética , Transativadores/metabolismo
17.
Mod Pathol ; 26(5): 648-57, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23307058

RESUMO

Combination antiretroviral therapy is highly effective in HIV infection, leading to decreased incidences of AIDS-defining neoplasms. However, HIV patients still have a 10-fold increased risk of developing classical Hodgkin lymphoma compared with the general population. As Hodgkin- and Reed-Sternberg cells represent only a minority in the tumor infiltrate, the aim of the present study was to characterize the microenvironment of HIV-related classical Hodgkin lymphoma and compare it with classical Hodgkin lymphoma cases of immunocompetent individuals. The major morphologic differences were the presence of necrotic foci and the absence of epithelioid cell formation in HIV-related Hodgkin lymphoma. We observed a significantly decreased number of CD4+ T-cells and a significantly increased number of CD163+ macrophages in HIV-related Hodgkin lymphoma. Cases exhibiting a 'sarcomatoid' pattern of the reactive infiltrate exhibited significantly greater numbers of macrophages, associating the 'sarcomatoid' pattern to the presence of spindle-shaped macrophages. Whereas, rosetting of CD4+ T-cells around Hodgkin- and Reed-Sternberg cells was frequently observed in classical Hodgkin lymphoma in immunocompetent persons; rosetting in a subset of HIV-related Hodgkin lymphoma cases appeared to involve cytoplasmic protrusions of spindle-shaped macrophages. HIV-related Hodgkin lymphoma, therefore, is characterized by unique morphologic features, which should be recognized by pathologists.


Assuntos
Linfócitos T CD4-Positivos/patologia , Infecções por HIV/complicações , HIV-1 , Doença de Hodgkin/patologia , Doença de Hodgkin/virologia , Macrófagos/patologia , Adulto , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Técnicas de Cocultura , Feminino , Infecções por HIV/patologia , Doença de Hodgkin/imunologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Receptores de Superfície Celular/metabolismo , Células de Reed-Sternberg/patologia
18.
Front Immunol ; 4: 380, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24409176

RESUMO

T-cell receptor (TCR) polyclonal mature T cells are surprisingly resistant to oncogenic transformation after retroviral insertion of T-cell oncogenes. In a mouse model, it has been shown that mature T-cell lymphoma/leukemia (MTCLL) is not induced upon transplantation of mature, TCR polyclonal wild-type (WT) T cells, transduced with gammaretroviral vectors encoding potent T-cell oncogenes, into RAG1-deficient recipients. However, further studies demonstrated that quasi-monoclonal T cells treated with the same protocol readily induced MTCLL in the recipient mice. It has been hypothesized that in the TCR polyclonal situation, outgrowth of preleukemic cells and subsequent conversion to overt malignancy is suppressed through regulation of clonal abundances on a per-clone basis due to interactions between TCRs and self-peptide-MHC-complexes (spMHCs), while these mechanisms fail in the quasi-monoclonal situation. To quantitatively study this hypothesis, we applied a mathematical modeling approach. In particular, we developed a novel ordinary differential equation model of T-cell homeostasis, in which T-cell fate depends on spMHC-TCR-interaction-triggered stimulatory signals from antigen-presenting cells (APCs). Based on our mathematical modeling approach, we identified parameter configurations of our model, which consistently explain the observed phenomena. Our results suggest that the preleukemic cells are less competent than healthy competitor cells in acquiring survival stimuli from APCs, but that proliferation of these preleukemic cells is less dependent on survival stimuli from APCs. These predictions now call for experimental validation.

19.
Mol Med ; 17(11-12): 1223-32, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21826372

RESUMO

Several cases of T-cell leukemia caused by gammaretroviral insertional mutagenesis in children treated for x-linked severe combined immunodeficiency (SCID) by transplantation of autologous gene-modified stem cells were reported. In a comparative analysis, we recently showed that mature T cells, on the contrary, are highly resistant to transformation by gammaretroviral gene transfer. In the present study, we observed immortalization of a single T-cell clone in vitro after gammaretroviral transduction of the T-cell protooncogene LMO2. This clone was CD4/CD8 double-negative, but expressed a single rearranged T-cell receptor. The clone was able to overgrow nonmanipulated competitor T-cell populations in vitro, but no tumor formation was observed after transplantation into Rag-1 deficient recipients. The retroviral integration site (RIS) was found to be near the IL2RA and IL15RA genes. As a consequence, both receptors were constitutively upregulated on the RNA and protein level and the immortalized cell clone was highly IL-2 dependent. Ectopic expression of both, the IL2RA chain and LMO2, induced long-term growth in cultured primary T cells. This study demonstrates that insertional mutagenesis can contribute to immortalization of mature T cells, although this is a rare event. Furthermore, the results show that signaling of the IL-2 receptor and the protooncogene LMO2 can act synergistically in maligniant transformation of mature T lymphocytes.


Assuntos
Diferenciação Celular/imunologia , Mutagênese Insercional/métodos , Retroviridae/genética , Linfócitos T/citologia , Linfócitos T/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Biomarcadores , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Transformada , Proliferação de Células/efeitos dos fármacos , Células Clonais , Vetores Genéticos/genética , Humanos , Interleucina-2/farmacologia , Proteínas com Domínio LIM/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Interleucina-15/metabolismo , Receptores de Interleucina-2/metabolismo , Retroviridae/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Transdução Genética , Integração Viral/efeitos dos fármacos
20.
Mol Ther ; 18(7): 1330-8, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20461062

RESUMO

T-cell-based adoptive immunotherapy is widely used to treat graft rejection and relapse after stem cell transplantation (SCT). However, this approach is hampered by a high risk of life-threatening graft-versus-host-disease (GvHD). Clinical trials have demonstrated the value of suicide genes to modify T cells for the effective control of GvHD. Herewith, we show that the combination of a codon-optimized B-cell antigen (CD20op) with a selection marker based on a cytoplasmic truncated version of the human stem cell antigen CD34 (tCD34) allows the generation of highly enriched gene-modified T cells. We demonstrate coordinate co-expression of both transgenes and high expression of CD20op resulting in an increased susceptibility to Rituximab (RTX)-induced cell death. In addition, T cells partially retained their alloreactive potential and their CD4/CD8 ratio after transduction and expansion. Long-lasting transgene expression was sustained in vivo after adoptive transfer into Rag-1(-/-) mice. Moreover, gene-modified T cells were quickly and efficiently depleted from peripheral blood (PB) and secondary lymphoid organs of transplanted animals after RTX treatment. These results warrant further steps toward a clinical application of CD20op as a suicide gene for adoptive immunotherapy.


Assuntos
Antígenos CD20/metabolismo , Antígenos CD34/metabolismo , Imunoterapia Adotiva/métodos , Linfócitos T/citologia , Linfócitos T/metabolismo , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Murinos , Linhagem Celular , Células Cultivadas , Vetores Genéticos/genética , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/terapia , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Rituximab , Linfócitos T/efeitos dos fármacos
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