RESUMO
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive mature T-cell malignancy characterized by marked lymphocytosis, B symptoms, lymphadenopathy, and hepatosplenomegaly. There is no standard treatment approach, and in the absence of an allogeneic transplant, the prognosis remains poor. The disease-defining cytogenetic abnormality in T-PLL is the juxtaposition of the TCL1-family oncogene to the TCR gene enhancer locus primarily due to an inversion of chromosome 14, that is, inv(14). The application of next-generation sequencing technologies led to the discovery of highly recurrent gain-of-function mutations in JAK1/3 and STAT5B in over 70% of T-PLL providing opportunities for therapeutic intervention using small molecule inhibitors. Additional genetic mechanisms that may contribute to the pathogenesis of T-PLL remain unknown. Herein we describe the identification of a novel gene fusion SMCHD1::JAK2 resulting from a translocation between chromosome 9 and 18 involving SMCHD1 exon 45 and JAK2 exon 14 (t(9;18)(p24.1;p11.32)(chr9:g.5080171::chr18:g.2793269)), a previously undescribed genetic event in a patient with T-PLL harboring the key disease defining inv(14) resulting in rearrangement of TCL1 and TRA/D. In this manuscript, we describe the clinical and genetic features of the patient's disease course over a 25-month post-treatment duration using ruxolitinib and duvelisib.
Assuntos
Janus Quinase 2 , Leucemia Prolinfocítica de Células T , Humanos , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/tratamento farmacológico , Leucemia Prolinfocítica de Células T/patologia , Janus Quinase 2/genética , Proteínas de Fusão Oncogênica/genética , Masculino , Translocação Genética , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Pessoa de Meia-Idade , Nitrilas/uso terapêutico , Cromossomos Humanos Par 9/genéticaRESUMO
Here we describe the case of a 69-year-old man who was found to have moderate thrombocytopenia and severe splenomegaly during a medical checkup at the age of 67. At the first visit, his white blood cell (WBC) count was 7,400/µl with 80% lymphocytes, and bone marrow aspiration showed 24% atypical lymphocytes. Flow cytometry of atypical lymphocytes was positive for mature T-cell markers, and T-cell clonality was revealed by T-cell receptor gene rearrangement. TCL1 was negative on immunohistochemistry. We diagnosed TCL1-family negative T-cell prolymphocytic leukemia (T-PLL) and employed watchful waiting. Thirty months after diagnosis, the patient developed urinary retention and right lower-limb paresis despite a normal WBC count, and an extradural tumor around the thoracic vertebrae and spinal cord compression were detected. The tumor was diagnosed as extranodal involvement of TCL1-family negative T-PLL, but the patient's general condition deteriorated rapidly, and no treatment was possible. T-PLL is a rare disease characterized by leukocytosis, and the WBC count generally increases with disease progression. Although blood counts are recommended for observation, it is important to keep in mind that the disease may worsen even if blood counts do not change.
Assuntos
Progressão da Doença , Leucemia Prolinfocítica de Células T , Humanos , Masculino , Idoso , Leucemia Prolinfocítica de Células T/diagnóstico , Leucemia Prolinfocítica de Células T/patologia , Contagem de Leucócitos , Proteínas Proto-OncogênicasRESUMO
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm that originates from mature post-thymic T-cells. Cutaneous manifestations are a common presentation in T-PLL but rarely are a presentation in the recurrent setting. Here, we describe the case of a 75-year-old female with a history of T-PLL-who at the time of initial diagnosis did not exhibit any rash-presenting with diffuse rash, facial swelling, sore throat, and dysphagia 7 months later and was found to have recurrent T-PLL. She had diffuse lymphadenopathy and diffuse skin lesions. Biopsy of the skin lesions also confirmed infiltration with T-PLL cells. After review of the literature, no previously reported cases of recurrent T-PLL presented as diffuse skin lesions. This case demonstrates that recurrent T-PLL may present with diffuse rash, respiratory distress, and anasarca. It is important to stay vigilant in patients with history of T-PLL to recognize signs of recurrent disease to allow prompt diagnosis and treatment.
Assuntos
Exantema , Leucemia Prolinfocítica de Células T , Dermatopatias , Neoplasias Cutâneas , Feminino , Humanos , Idoso , Leucemia Prolinfocítica de Células T/diagnóstico , Leucemia Prolinfocítica de Células T/patologia , Leucemia Prolinfocítica de Células T/terapia , Pele/patologia , Neoplasias Cutâneas/patologia , Exantema/patologiaRESUMO
OBJECTIVES: T-cell prolymphocytic leukemia (T-PLL) is a rare mature T-cell leukemia usually characterized by inv(14)(q11.2q32)/t(14;14)(q11.2;q32). In this study, we aimed to investigate the clinicopathologic features and molecular profile of T-PLL associated with t(X;14)(q28;q11.2). METHODS: The study group included 10 women and 5 men with a median age of 64 years. All 15 patients had a diagnosis of T-PLL with t(X;14)(q28;q11.2). RESULTS: All 15 patients had lymphocytosis at initial diagnosis. Morphologically, the leukemic cells had features of prolymphocytes in 11 patients, small cell variant in 3, and cerebriform variant in 1. All 15 patients had hypercellular bone marrow with an interstitial infiltrate in 12 (80%) cases. By flow cytometry, the leukemic cells were surface CD3+/CD5+/CD7+/CD26+/CD52+/TCR α/ß+â in 15 (100%) cases, CD2+â in 14 (93%) cases, CD4+/CD8+â in 8 (53%) cases, CD4+/CD8- in 6 (40%) cases, and CD4-/CD8â +â in 1 (7%) case. At the cytogenetic level, complex karyotypes with t(X;14)(q28;q11.2) were seen in all 15 patients assessed. Mutational analysis showed mutations of JAK3 in 5 of 6 and STAT5B p.N642H in 2 of 6 patients. Patients received variable treatments, including 12 with alemtuzumab. After a median follow-up of 17.2 months, 8 of 15 (53%) patients died. CONCLUSIONS: T-PLL with t(X;14)(q28;q11.2) frequently shows a complex karyotype and mutations involving JAK/STAT pathway, and it is an aggressive disease with a poor outcome.
Assuntos
Janus Quinase 3 , Leucemia Prolinfocítica de Células T , Fator de Transcrição STAT5 , Leucemia Prolinfocítica de Células T/tratamento farmacológico , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/patologia , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Resultado do Tratamento , Linfocitose/patologia , Análise Mutacional de DNA , Janus Quinase 3/genética , Fator de Transcrição STAT5/genética , MutaçãoRESUMO
T-prolymphocytic leukemia (T-PLL) is a rare, aggressive T-cell leukemia, and patients typically present with marked peripheral blood lymphocytosis. Approximately 15-20 % of patients may present with moderate and relative stable lymphocytosis and an indolent clinical course that can persist for a few years. However, eventually these patients go on to develop marked lymphocytosis and rapidly progressive disease. We report a 72-year-old man who presented with multicompartmental lymphadenopathy and a normal complete blood count. Excision of left and right cervical lymph nodes showed replacement of the lymph node architecture by a small T-cell neoplasm positive for CD3, CD4, CD5, CD7 and TCL-1, and negative for CD8, CD20, CD30 and ALK. Subsequent bone marrow evaluation showed minimal bone marrow involvement by a T-cell neoplasm associated with TCL1A rearrangement in 11 % of cells supporting the diagnosis of T-PLL. Despite treatment, he showed progressive lymphadenopathy while remarkably maintaining normal white blood cell counts until he eventually developed leukocytosis of 110.9 × 103/uL 26 months later. Review of the literature identified only a single abstract reporting a patient with a similar lymphoma-like presentation and normal white blood cell count; however, that case showed significant bone marrow involvement in stark contrast to the current case. In summary, we report a highly unusual case of T-PLL can initially presenting with an aleukemic or lymphoma-like clinical picture, which can make establishing the diagnosis challenging.
Assuntos
Leucemia Prolinfocítica de Células T , Leucemia Prolinfocítica , Linfadenopatia , Linfocitose , Masculino , Humanos , Idoso , Linfocitose/patologia , Leucemia Prolinfocítica/patologia , Leucemia Prolinfocítica de Células T/diagnóstico , Leucemia Prolinfocítica de Células T/patologia , Medula Óssea/patologia , Linfadenopatia/patologiaRESUMO
T-cell prolymphocytic leukemia (T-PLL) is a rare blood cancer with poor prognosis. Overexpression of the proto-oncogene TCL1A and missense mutations of the tumor suppressor ATM are putative main drivers of T-PLL development, but so far only little is known about the existence of T-PLL gene expression subtypes. We performed an in-depth computational reanalysis of 68 gene expression profiles of one of the largest currently existing T-PLL patient cohorts. Hierarchical clustering combined with bootstrapping revealed three robust T-PLL gene expression subgroups. Additional comparative analyses revealed similarities and differences of these subgroups at the level of individual genes, signaling and metabolic pathways, and associated gene regulatory networks. Differences were mainly reflected at the transcriptomic level, whereas gene copy number profiles of the three subgroups were much more similar to each other, except for few characteristic differences like duplications of parts of the chromosomes 7, 8, 14, and 22. At the network level, most of the 41 predicted potential major regulators showed subgroup-specific expression levels that differed at least in comparison to one other subgroup. Functional annotations suggest that these regulators contribute to differences between the subgroups by altering processes like immune responses, angiogenesis, cellular respiration, cell proliferation, apoptosis, or migration. Most of these regulators are known from other cancers and several of them have been reported in relation to leukemia (e.g. AHSP, CXCL8, CXCR2, ELANE, FFAR2, G0S2, GIMAP2, IL1RN, LCN2, MBTD1, PPP1R15A). The existence of the three revealed T-PLL subgroups was further validated by a classification of T-PLL patients from two other smaller cohorts. Overall, our study contributes to an improved stratification of T-PLL and the observed subgroup-specific molecular characteristics could help to develop urgently needed targeted treatment strategies.
Assuntos
Leucemia Prolinfocítica de Células T , Leucemia Prolinfocítica , Proteínas Sanguíneas/genética , Proteínas Cromossômicas não Histona/genética , GTP Fosfo-Hidrolases/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Leucemia Prolinfocítica/genética , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/patologia , Proteínas de Membrana/genética , Chaperonas Moleculares/genética , Proteínas/genética , Transdução de Sinais , TranscriptomaRESUMO
T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-refractory T-cell malignancy with limited therapeutic options and a poor prognosis. Current disease concepts implicate TCL1A oncogene-mediated enhanced T-cell receptor (TCR) signaling and aberrant DNA repair as central perturbed pathways. We discovered that recurrent gains on chromosome 8q more frequently involve the argonaute RISC catalytic component 2 (AGO2) gene than the adjacent MYC locus as the affected minimally amplified genomic region. AGO2 has been understood as a protumorigenic key regulator of miRNA (miR) processing. Here, in primary tumor material and cell line models, AGO2 overrepresentation associated (i) with higher disease burden, (ii) with enhanced in vitro viability and growth of leukemic T cells, and (iii) with miR-omes and transcriptomes that highlight altered survival signaling, abrogated cell-cycle control, and defective DNA damage responses. However, AGO2 elicited also immediate, rather non-RNA-mediated, effects in leukemic T cells. Systems of genetically modulated AGO2 revealed that it enhances TCR signaling, particularly at the level of ZAP70, PLCγ1, and LAT kinase phosphoactivation. In global mass spectrometric analyses, AGO2 interacted with a unique set of partners in a TCR-stimulated context, including the TCR kinases LCK and ZAP70, forming membranous protein complexes. Models of their three-dimensional structure also suggested that AGO2 undergoes posttranscriptional modifications by ZAP70. This novel TCR-associated noncanonical function of AGO2 represents, in addition to TCL1A-mediated TCR signal augmentation, another enhancer mechanism of this important deregulated growth pathway in T-PLL. These findings further emphasize TCR signaling intermediates as candidates for therapeutic targeting. SIGNIFICANCE: The identification of AGO2-mediated activation of oncogenic T cells through signal amplifying protein-protein interactions advances the understanding of leukemogenic AGO2 functions and underlines the role of aberrant TCR signaling in T-PLL.
Assuntos
Leucemia Prolinfocítica de Células T , MicroRNAs , Humanos , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Fosforilação , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/genética , Linfócitos T/metabolismoRESUMO
T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic mature T-cell malignancy. It typically presents with exponentially rising lymphocyte counts, splenomegaly, and bone marrow infiltration. Effective treatment options are scarce and a better understanding of TPLL's pathogenesis is desirable. Activation of the TCL1 proto-oncogene and loss-of-function perturbations of the tumor suppressor ATM are TPLL's genomic hallmarks. The leukemic cell reveals a phenotype of active T-cell receptor (TCR) signaling and aberrant DNA damage responses. Regulatory networks based on the profile of microRNA (miR) have not been described for T-PLL. In a combined approach of small-RNA and transcriptome sequencing in 46 clinically and moleculary well-characterized T-PLL, we identified a global T-PLL-specific miR expression profile that involves 34 significantly deregulated miR species. This pattern strikingly resembled miR-ome signatures of TCR-activated T cells. By integrating these T-PLL miR profiles with transcriptome data, we uncovered regulatory networks associated with cell survival signaling and DNA damage response pathways. Despite a miR-ome that discerned leukemic from normal T cells, there were also robust subsets of T-PLL defined by a small set of specific miR. Most prominently, miR-141 and the miR- 200c-cluster separated cases into two major subgroups. Furthermore, increased expression of miR-223-3p as well as reduced expression of miR-21 and the miR-29 cluster were associated with more activated Tcell phenotypes and more aggressive disease presentations. Based on the implicated pathobiological role of these miR deregulations, targeting strategies around their effectors appear worth pursuing. We also established a combinatorial miR-based overall survival score for T-PLL (miROS-T-PLL), that might improve current clinical stratifications.
Assuntos
Leucemia Prolinfocítica de Células T , MicroRNAs , Dano ao DNA , Humanos , Leucemia Prolinfocítica de Células T/tratamento farmacológico , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/patologia , Ativação Linfocitária , MicroRNAs/genética , Linfócitos TAssuntos
Cromossomos Humanos Par 14/genética , Cromossomos Humanos X/genética , Cistos , Leucemia Prolinfocítica de Células T , Translocação Genética , Idoso , Cistos/diagnóstico , Cistos/genética , Cistos/metabolismo , Cistos/patologia , Feminino , Humanos , Cariotipagem , Leucemia Prolinfocítica de Células T/diagnóstico , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/metabolismo , Leucemia Prolinfocítica de Células T/patologia , Glândula Parótida/metabolismo , Glândula Parótida/patologiaRESUMO
We report a 52-year-old man who presented with erythroderma and nodular lesions on face manifesting as "Leonine facies". He had impaired sensation over the face and was initially diagnosed to have lepromatous leprosy and was treated with antileprosy drugs. Investigations showed a total Leukocyte count of 550 X 109/l with 90% atypical lymphoid cells with prominent central nucleolus suggestive of prolymphocytes. On flow cytometry, these cells were positive for cytoplasmic CD3, CD2, CD5, CD7, CD4, and CD38 (dim) and were negative for CD1a and TdT and diagnosis of T-prolymphocytic leukemia was made.
Assuntos
Dermatite Esfoliativa/patologia , Leucemia Prolinfocítica de Células T/diagnóstico , Leucemia Prolinfocítica de Células T/patologia , Antígenos CD/análise , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Dermatite Esfoliativa/diagnóstico , Doxorrubicina/uso terapêutico , Fácies , Humanos , Leucemia Prolinfocítica de Células T/tratamento farmacológico , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Pele/patologia , Vincristina/uso terapêuticoRESUMO
T-cell prolymphocytic leukemia (T-PLL) is an aggressive post-thymic T-cell malignancy, which accounts for 2% of mature lymphocytic leukemias in adults. Though typically presenting with a brief history of B symptoms, hepatosplenomegaly, and marked lymphocytosis, erythematous or nodular skin rashes involving the trunk or limbs may be seen in 25% to 30% of patients, as well as a purpuric rash in a periorbital distribution. Cutaneous involvement typically presents in the context of patients with an established history of T-PLL, but it can less frequently present as an initial symptom heralding the diagnosis. An unusual case of T-PLL is described, presenting initially as palmoplantar ulcerated nodules with an initial biopsy suggestive of perniosis, followed by rapid progression of dark violaceous and bright red papules throughout the body after initiation of obinutuzumab. The diagnosis of T-PLL was subsequently fully supported by the clinical, laboratory, cytologic, and immunophenotypic findings. This case highlights the importance of a multidisciplinary team approach to address such rare and atypical presentations.
Assuntos
Leucemia Prolinfocítica de Células T/patologia , Vasculite/patologia , Idoso , Pérnio/diagnóstico , Pérnio/patologia , Diagnóstico Diferencial , Feminino , Humanos , Leucemia Prolinfocítica de Células T/diagnóstico , Vasculite/diagnósticoRESUMO
T cell prolymphocytic leukemia (T-PLL) is a rare disease with aggressive clinical course. Cytogenetic analysis, whole-exome and whole-genome sequencing have identified primary structural alterations in T-PLL, including inversion, translocation and copy number variation. Recurrent somatic mutations were also identified in genes encoding chromatin regulators and those in the JAK-STAT signaling pathway. Epigenetic alterations are the hallmark of many cancers. However, genome-wide epigenomic profiles have not been reported in T-PLL, limiting the mechanistic study of its carcinogenesis. We hypothesize epigenetic mechanisms also play a key role in T-PLL pathogenesis. To systematically test this hypothesis, we generated genome-wide maps of regulatory regions using H3K4me3 and H3K27ac ChIP-seq, as well as RNA-seq data in both T-PLL patients and healthy individuals. We found that genes down-regulated in T-PLL are mainly associated with defense response, immune system or adaptive immune response, while up-regulated genes are enriched in developmental process, as well as WNT signaling pathway with crucial roles in cell fate decision. In particular, our analysis revealed a global alteration of regulatory landscape in T-PLL, with differential peaks highly enriched for binding motifs of immune related transcription factors, supporting the epigenetic regulation of oncogenes and genes involved in DNA damage response and T-cell activation. Together, our work reveals a causal role of epigenetic dysregulation in T-PLL.
Assuntos
Reprogramação Celular/genética , Epigênese Genética/genética , Epigênese Genética/fisiologia , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/patologia , Transcrição Gênica/genética , Variações do Número de Cópias de DNA , Dano ao DNA/genética , Estudo de Associação Genômica Ampla , Humanos , Leucemia Prolinfocítica de Células T/imunologia , Ativação Linfocitária/genética , Linfócitos T/imunologia , Via de Sinalização Wnt/fisiologiaRESUMO
ABSTRACT: T-cell prolymphocytic leukemia (TPLL) is a rare form of leukemia by T lymphocytes at a post-thymic intermediate stage of development with an α/ß immunophenotype. Facial involvement is common in TPLL and displays significant heterogeneity of the lesions' description and location. TPLL also contains a wide array of histology findings, cell cytology, and molecular studies. Here, we describe a TPLL patient who presented with an ill-defined erythematous patch involving the right axilla progressing to the left axilla, upper back, and face that resembled dermatomyositis. The diagnosis of TPLL was established using flow cytometry of bone marrow and peripheral blood, and histopathology of the involved skin. Dermatologists should be aware of these unique features.
Assuntos
Dermatomiosite/patologia , Leucemia Prolinfocítica de Células T/patologia , Neoplasias Cutâneas/patologia , Alemtuzumab/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biópsia , Diagnóstico Diferencial , Feminino , Humanos , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/imunologia , Leucemia Prolinfocítica de Células T/terapia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Transplante de Células-Tronco , Resultado do TratamentoRESUMO
Conventional therapies for patients with T-cell prolymphocytic leukemia (T-PLL), such as cytotoxic chemotherapy and alemtuzumab, have limited efficacy and considerable toxicity. Several novel agent classes have demonstrated preclinical activity in T-PLL, including inhibitors of the JAK/STAT and T-cell receptor pathways, as well as histone deacetylase (HDAC) inhibitors. Recently, the BCL-2 inhibitor venetoclax also showed some clinical activity in T-PLL. We sought to characterize functional apoptotic dependencies in T-PLL to identify a novel combination therapy in this disease. Twenty-four samples from patients with primary T-PLL were studied by using BH3 profiling, a functional assay to assess the propensity of a cell to undergo apoptosis (priming) and the relative dependence of a cell on different antiapoptotic proteins. Primary T-PLL cells had a relatively low level of priming for apoptosis and predominantly depended on BCL-2 and MCL-1 proteins for survival. Selective pharmacologic inhibition of BCL-2 or MCL-1 induced cell death in primary T-PLL cells. Targeting the JAK/STAT pathway with the JAK1/2 inhibitor ruxolitinib or HDAC with belinostat both independently increased dependence on BCL-2 but not MCL-1, thereby sensitizing T-PLL cells to venetoclax. Based on these results, we treated 2 patients with refractory T-PLL with a combination of venetoclax and ruxolitinib. We observed a deep response in JAK3-mutated T-PLL and a stabilization of the nonmutated disease. Our functional, precision-medicine-based approach identified inhibitors of HDAC and the JAK/STAT pathway as promising combination partners for venetoclax, warranting a clinical exploration of such combinations in T-PLL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Leucemia Prolinfocítica de Células T/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Neoplasias , Idoso , Idoso de 80 Anos ou mais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Feminino , Humanos , Leucemia Prolinfocítica de Células T/metabolismo , Leucemia Prolinfocítica de Células T/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Nitrilas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologiaRESUMO
Novel targeted agents used in therapy of lymphoid malignancies, such as inhibitors of B-cell receptor-associated kinases, are recognized to have complex immune-mediated effects. NEDD8-activating enzyme (NAE) has been identified as a tractable target in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. We and others have shown that pevonedistat (TAK-924), a small-molecule inhibitor of NAE, abrogates NF-κB signaling in malignant B cells. However, NF-κB pathway activity is indispensable in immune response, and T-cell function is altered in patients with CLL. Using T cells derived from patients with CLL, we demonstrate that although targeting NAE results in markedly differential expression of NF-κB-regulated genes and downregulation of interleukin (IL)-2 signaling during T-cell activation, T cells evade apoptosis. Meanwhile, NAE inhibition favorably modulates polarization of T cells in vitro, with decreased Treg differentiation and a shift toward TH1 phenotype, accompanied by increased interferon-γ production. These findings were recapitulated in vivo in immunocompetent mouse models. T cells exposed to pevonedistat in washout experiments, informed by its human pharmacokinetic profile, recover NAE activity, and maintain their response to T-cell receptor stimulation and cytotoxic potential. Our data shed light on the potential immune implications of targeting neddylation in CLL and lymphoid malignancies.
Assuntos
Antineoplásicos/farmacologia , Ciclopentanos/farmacologia , Imunomodulação/efeitos dos fármacos , Leucemia Prolinfocítica de Células T/imunologia , Leucemia Prolinfocítica de Células T/metabolismo , Proteína NEDD8/antagonistas & inibidores , Proteína NEDD8/metabolismo , Pirimidinas/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Ciclopentanos/uso terapêutico , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Leucemia Prolinfocítica de Células T/tratamento farmacológico , Leucemia Prolinfocítica de Células T/patologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Modelos Biológicos , Pirimidinas/uso terapêutico , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic neoplasm. Differentiation stage and immune-effector functions of the underlying tumor cell are insufficiently characterized. Constitutive activation of the T-cell leukemia 1A (TCL1A) oncogene distinguishes the (pre)leukemic cell from regular postthymic T cells. We assessed activation-response patterns of the T-PLL lymphocyte and interrogated the modulatory impact by TCL1A. Immunophenotypic and gene expression profiles revealed a unique spectrum of memory-type differentiation of T-PLL with predominant central-memory stages and frequent noncanonical patterns. Virtually all T-PLL expressed a T-cell receptor (TCR) and/or CD28-coreceptor without overrepresentation of specific TCR clonotypes. The highly activated leukemic cells also revealed losses of negative-regulatory TCR coreceptors (eg, CTLA4). TCR stimulation of T-PLL cells evoked higher-than-normal cell-cycle transition and profiles of cytokine release that resembled those of normal memory T cells. More activated phenotypes and higher TCL1A correlated with inferior clinical outcomes. TCL1A was linked to the marked resistance of T-PLL to activation- and FAS-induced cell death. Enforced TCL1A enhanced phospho-activation of TCR kinases, second-messenger generation, and JAK/STAT or NFAT transcriptional responses. This reduced the input thresholds for IL-2 secretion in a sensitizer-like fashion. Mice of TCL1A-initiated protracted T-PLL development resembled such features. When equipped with epitope-defined TCRs or chimeric antigen receptors, these Lckpr-hTCL1Atg T cells gained a leukemogenic growth advantage in scenarios of receptor stimulation. Overall, we propose a model of T-PLL pathogenesis in which TCL1A enhances TCR signals and drives the accumulation of death-resistant memory-type cells that use amplified low-level stimulatory input, and whose loss of negative coregulators additionally maintains their activated state. Treatment rationales are provided by combined interception in TCR and survival signaling.
Assuntos
Memória Imunológica , Leucemia Prolinfocítica de Células T/imunologia , Proteínas Proto-Oncogênicas/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Animais , Humanos , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/patologia , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas/genética , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais/genética , Linfócitos T/patologiaRESUMO
T-cell prolymphocytic leukemia (T-PLL) is a rare T-cell leukemia characterized in many patients by marked peripheral lymphocytosis, prominent splenomegaly, and skin lesions. The differential diagnosis is broad and includes other T-cell disorders presenting with similar clinical findings. This review addresses (a) the natural history, demographics, and genetic features of T-PLL; (b) clinical and pathologic differential diagnostic considerations; and (c) recent developments in the T-PLL literature relevant to laboratory professionals.