RESUMO
Mature T-cell and NK-cell leukemias represent a clinically heterogeneous group of diseases, ranging from indolent expansions of large granular lymphocytes, to aggressive diseases that are associated with a fulminant clinical course. Recent advances in genomic methodologies have massively increased the understanding of the pathogenesis of this group of diseases. While the entities are genetically heterogeneous, JAK-STAT pathway activation appears to be important across these disorders. The identification of constitutively activated pathways and the emergence of novel targeted pharmaceutical agents raise the expectation that more effective therapies will be identified for these disorders in the coming years.
Assuntos
Leucemia de Células T , HumanosRESUMO
Identification of biomarkers and therapeutic targets is a critical goal of precision medicine. N-glycoproteins are a particularly attractive class of proteins that constitute potential cancer biomarkers and therapeutic targets for small molecules, antibodies, and cellular therapies. Using mass spectrometry (MS), we generated a compendium of 1,091 N-glycoproteins (from 40 human primary lymphomas and cell lines). Hierarchical clustering revealed distinct subtype signatures that included several subtype-specific biomarkers. Orthogonal immunological studies in 671 primary lymphoma tissue biopsies and 32 lymphoma-derived cell lines corroborated MS data. In anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma (ALCL), integration of N-glycoproteomics and transcriptome sequencing revealed an ALK-regulated cytokine/receptor signaling network, including vulnerabilities corroborated by a genome-wide clustered regularly interspaced short palindromic screen. Functional targeting of IL-31 receptor ß, an ALCL-enriched and ALK-regulated N-glycoprotein in this network, abrogated ALK+ALCL growth in vitro and in vivo. Our results highlight the utility of functional proteogenomic approaches for discovery of cancer biomarkers and therapeutic targets.
Assuntos
Biomarcadores Tumorais/genética , Linfoma/genética , Transcriptoma/genética , Linhagem Celular Tumoral , Humanos , Proteogenômica/métodos , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais/genéticaRESUMO
Optimal salvage therapy for primary refractory peripheral T-cell lymphomas (PTCL) and the role of hematopoietic stem cell transplant (SCT) remain poorly defined. We conducted a retrospective review of clinical outcomes and prognostic factors in a single-center cohort of 93 patients with primary refractory PTCL, defined as progression during first-line therapy or relapse within 6 months of its completion. Clinical outcomes were poor in this population, with median event-free survival (EFS) of 3.5 months, median overall survival (OS) of 9.1 months, and 34% 3-year survival. Outcomes were comparable in patients who progressed through first-line therapy and patients who achieved CR/PR and subsequently relapsed within 6 months. A majority exhibited high-risk features and had intermediate to high risk IPI, which correlated with inferior outcomes. There was no difference in outcomes between patients who received single-agent salvage regimens and patients who underwent traditional, multi-agent salvage regimens. Thus, participation in well-designed clinical trials should be encouraged in this population. Additionally, there may be a trend toward improved EFS and OS in patients who underwent autologous or allogeneic SCT compared to patients who achieved CR or PR but were not transplanted.
Assuntos
Linfoma de Células T Periférico/tratamento farmacológico , Terapia de Salvação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Linfoma de Células T Periférico/mortalidade , Linfoma de Células T Periférico/terapia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Estudos Retrospectivos , Risco , Adulto JovemAssuntos
Neoplasias Abdominais/patologia , Virilha , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Neoplasias Abdominais/genética , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Células Epitelioides/patologia , Éxons , Fusão Gênica , Humanos , Masculino , Chaperonas Moleculares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/genéticaRESUMO
The transcription factor GATA-3, highly expressed in many cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphomas (PTCL), confers resistance to chemotherapy in a cell-autonomous manner. As GATA-3 is transcriptionally regulated by NF-κB, we sought to determine the extent to which proteasomal inhibition impairs NF-κB activation and GATA-3 expression and cell viability in malignant T cells. Proteasome inhibition, NF-κB activity, GATA-3 expression, and cell viability were examined in patient-derived cell lines and primary T-cell lymphoma specimens ex vivo treated with the oral proteasome inhibitor ixazomib. Significant reductions in cell viability, NF-κB activation, and GATA-3 expression were observed preclinically in ixazomib-treated cells. Therefore, an investigator-initiated, single-center, phase II study with this agent in patients with relapsed/refractory CTCL/PTCL was conducted. Concordant with our preclinical observations, a significant reduction in NF-κB activation and GATA-3 expression was observed in an exceptional responder following one month of treatment with ixazomib. While ixazomib had limited activity in this small and heterogeneous cohort of patients, inhibition of the NF-κB/GATA-3 axis in a single exceptional responder suggests that ixazomib may have utility in appropriately selected patients or in combination with other agents.
Assuntos
Compostos de Boro/uso terapêutico , Glicina/análogos & derivados , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma de Células T Periférico/tratamento farmacológico , Terapia de Salvação/métodos , Idoso , Compostos de Boro/farmacologia , Linhagem Celular Tumoral , Feminino , Fator de Transcrição GATA3/efeitos dos fármacos , Fator de Transcrição GATA3/farmacologia , Glicina/farmacologia , Glicina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , NF-kappa B/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Células Tumorais CultivadasRESUMO
The cell of origin and the tumor microenvironment's role remain elusive for the most common peripheral T-cell lymphomas (PTCLs). As macrophages promote the growth and survival of malignant T cells and are abundant constituents of the tumor microenvironment, their functional polarization was examined in T-cell lymphoproliferative disorders. Cytokines that are abundant within the tumor microenvironment, particularly interleukin (IL)-10, were observed to promote alternative macrophage polarization. Macrophage polarization was signal transducer and activator of transcription 3 dependent and was impaired by the Janus kinase inhibitor ruxolitinib. In conventional T cells, the production of T helper (Th)2-associated cytokines and IL-10, both of which promote alternative macrophage polarization, is regulated by the T-cell transcription factor GATA-binding protein 3 (GATA-3). Therefore, its role in the T-cell lymphomas was examined. GATA-3 expression was observed in 45% of PTCLs, not otherwise specified (PTCL, NOS) and was associated with distinct molecular features, including the production of Th2-associated cytokines. In addition, GATA-3 expression identified a subset of PTCL, NOS with distinct clinical features, including inferior progression-free and overall survival. Collectively, these data suggest that further understanding the cell of origin and lymphocyte ontogeny among the T-cell lymphomas may improve our understanding of the tumor microenvironment's pathogenic role in these aggressive lymphomas.
Assuntos
Fator de Transcrição GATA3/genética , Interleucina-10/genética , Linfoma de Células T Periférico/genética , Microambiente Tumoral/genética , Western Blotting , Linhagem Celular Tumoral , Citocinas/genética , Citocinas/metabolismo , Fator de Transcrição GATA3/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Interleucina-10/metabolismo , Estimativa de Kaplan-Meier , Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Nitrilas , Pirazóis/farmacologia , Pirimidinas , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Linfócitos T/metabolismo , Linfócitos T/patologia , Células Th2/metabolismo , Células Th2/patologiaRESUMO
The spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Chromosomal translocations targeting tyrosine kinases in CD30-positive LPDs have not been described. Using whole-transcriptome sequencing, we identified a chimeric fusion involving NPM1 (5q35) and TYK2 (19p13) that encodes an NPM1-TYK2 protein containing the oligomerization domain of NPM1 and an intact catalytic domain in TYK2. Fluorescence in situ hybridization revealed NPM1-TYK2 fusions in 2 of 47 (4%) primary cases of CD30-positive LPDs and was absent in other mature T-cell neoplasms (n = 151). Functionally, NPM1-TYK2 induced constitutive TYK2, signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activation. Conversely, a kinase-defective NPM1-TYK2 mutant abrogated STAT1/3/5 signaling. Finally, short hairpin RNA-mediated silencing of TYK2 abrogated lymphoma cell growth. This is the first report of recurrent translocations involving TYK2, and it highlights the novel therapeutic opportunities in the treatment of CD30-positive LPDs with TYK2 translocations.
Assuntos
Antígeno Ki-1/genética , Linfoma Anaplásico Cutâneo Primário de Células Grandes/genética , Papulose Linfomatoide/genética , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias Cutâneas/genética , TYK2 Quinase/genética , Western Blotting , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Hibridização in Situ Fluorescente , Antígeno Ki-1/metabolismo , Linfoma Anaplásico Cutâneo Primário de Células Grandes/metabolismo , Linfoma Anaplásico Cutâneo Primário de Células Grandes/patologia , Papulose Linfomatoide/metabolismo , Papulose Linfomatoide/patologia , Mutação , Proteínas Nucleares/metabolismo , Nucleofosmina , Fusão Oncogênica , Proteínas de Fusão Oncogênica/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , TYK2 Quinase/metabolismo , Transcriptoma/genéticaRESUMO
The comprehensive genetic alterations underlying the pathogenesis of T-cell prolymphocytic leukemia (T-PLL) are unknown. To address this, we performed whole-genome sequencing (WGS), whole-exome sequencing (WES), high-resolution copy-number analysis, and Sanger resequencing of a large cohort of T-PLL. WGS and WES identified novel mutations in recurrently altered genes not previously implicated in T-PLL including EZH2, FBXW10, and CHEK2. Strikingly, WGS and/or WES showed largely mutually exclusive mutations affecting IL2RG, JAK1, JAK3, or STAT5B in 38 of 50 T-PLL genomes (76.0%). Notably, gain-of-function IL2RG mutations are novel and have not been reported in any form of cancer. Further, high-frequency mutations in STAT5B have not been previously reported in T-PLL. Functionally, IL2RG-JAK1-JAK3-STAT5B mutations led to signal transducer and activator of transcription 5 (STAT5) hyperactivation, transformed Ba/F3 cells resulting in cytokine-independent growth, and/or enhanced colony formation in Jurkat T cells. Importantly, primary T-PLL cells exhibited constitutive activation of STAT5, and targeted pharmacologic inhibition of STAT5 with pimozide induced apoptosis in primary T-PLL cells. These results for the first time provide a portrait of the mutational landscape of T-PLL and implicate deregulation of DNA repair and epigenetic modulators as well as high-frequency mutational activation of the IL2RG-JAK1-JAK3-STAT5B axis in the pathogenesis of T-PLL. These findings offer opportunities for novel targeted therapies in this aggressive leukemia.
Assuntos
Leucemia Prolinfocítica de Células T/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Sequência de Bases , Morte Celular/efeitos dos fármacos , Estudos de Coortes , Simulação por Computador , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , DNA de Neoplasias/genética , Exoma , Feminino , Humanos , Subunidade gama Comum de Receptores de Interleucina/genética , Janus Quinase 1/genética , Janus Quinase 3/química , Janus Quinase 3/genética , Leucemia Prolinfocítica de Células T/tratamento farmacológico , Leucemia Prolinfocítica de Células T/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Pimozida/farmacologia , Conformação Proteica , Fator de Transcrição STAT5/antagonistas & inibidores , Fator de Transcrição STAT5/química , Fator de Transcrição STAT5/genética , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Células Tumorais CultivadasRESUMO
We report a 4-year-old female who presented with severe hypereosinophilia (215.7 K/µl) and end-organ dysfunction. Extensive evaluation including whole exome sequencing was performed, revealing no causative mutation. Initial treatment with corticosteroids, leukapheresis, and hydroxyurea decreased her absolute eosinophil count (AEC), although it remained elevated. Despite the absence of a PDGFRA mutation, an imatinib trial resulted in normalization of her AEC. Imatinib was discontinued after sustained normal counts for 1 month. AECs have remained normal for more than 1 year off therapy. This provides support for consideration of imatinib in the treatment of hypereosinophilia even in the absence of a known tyrosine kinase mutation.
Assuntos
Síndrome Hipereosinofílica/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/análise , Pré-Escolar , Feminino , Humanos , Síndrome Hipereosinofílica/genética , Inibidores de Proteínas Quinases/uso terapêutico , Análise de Sequência de DNAAssuntos
Leucemia Mieloide Aguda/genética , Translocação Genética/genética , Idoso , Feminino , HumanosRESUMO
Myeloid neoplasm with eosinophilia and abnormalities of Alpha type platelet derived growth factor receptor (PDGFRA) is a type of hypereosinophilic syndrome characterized by multiorgan damage due to eosinophilia. Its association with thrombotic thrombocytopenic purpura (TTP) has rarely been reported. We describe here a case report of a female in whom TTP presented as one of the earlier manifestations of myeloproliferative HES with rearrangement of PDGFRA. Our patient was found to have a normal ADAMTS-13 level which is not commonly seen with TTP. This case illustrates the importance of recognizing the atypical presentations of HES which may be difficult to recognize.
Assuntos
Síndrome Hipereosinofílica/diagnóstico , Transtornos Mieloproliferativos/diagnóstico , Proteínas de Fusão Oncogênica/genética , Púrpura Trombocitopênica Trombótica/diagnóstico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Fatores de Poliadenilação e Clivagem de mRNA/genética , Adulto , Feminino , Rearranjo Gênico , Humanos , Síndrome Hipereosinofílica/genética , Transtornos Mieloproliferativos/genéticaRESUMO
OBJECTIVES: Two new classifications of myeloid neoplasms have recently been published: the International Consensus Classification (ICC) and the 5th edition of the World Health Organization classification (WHO5). We sought to examine the real-world impact of dueling classifications on patient diagnoses. METHODS: Our institutional pathology database was searched, and 237 specimens with a diagnosis of myeloid neoplasia were randomly selected. For each case, a classification based on the WHO5 and the ICC was assigned. The WHO5 and ICC diagnoses were compared to determine their degree of concordance. RESULTS: After applying the WHO5 and ICC diagnostic criteria, 134 (56.5%) cases were classified as concordant, 63 (26.6%) cases had terminological differences, 37 (15.6%) cases had minor diagnostic discrepancies, and 3 (1.3%) cases had major diagnostic discrepancies. Cases with minor diagnostic discrepancies included 25 cases of myelodysplastic syndrome (MDS), 10 cases of acute myeloid leukemia (AML), and 2 cases of myeloid precursor lesions. Cases with major diagnostic discrepancies included 2 cases that were diagnosed as MDS, not otherwise specified (NOS), according to the ICC but classified as AML with NPM1 alteration and AML with RBM15::MRTFA according to the WHO5 and 1 case that was characterized as chronic myelomonocytic leukemia according to the ICC and as AML with NPM1 alteration according to the WHO5. CONCLUSIONS: This study confirms that a majority of cases are classified similarly using the 2 systems. Given the overall similarity of the systems, future harmonization of the classifications should be pursued to avoid confusion and multiple diagnoses.
Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Humanos , Consenso , Transtornos Mieloproliferativos/diagnóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/diagnóstico , Organização Mundial da Saúde , Proteínas NuclearesRESUMO
OBJECTIVES: IDH1 and IDH2 are among the most commonly mutated genes in myeloid neoplasms (MNs). It has been proposed that IDH2 R172 mutations (mR172) define a molecular subtype of acute myeloid leukemia (AML), but the clinicopathologic features of AML with mR172 have not been fully described. METHODS: We retrospectively identified and characterized all mR172 MNs with increased blasts in our archive for comparison to a similar number of MNs with IDH2 R140 (mR140) and IDH1 R132 (mR132) mutations (n = 39). RESULTS: mR172 cases had lower leukocyte counts and bone marrow cellularity than did non-mR172 cases. mR172 MNs often displayed blasts with highly invaginated, cleaved nuclei and typically expressed CD34, HLA-DR, CD117, and CD13 but often with diminished CD33. mR172 cases often had co-occurring mutations in myelodysplasia-associated genes and/or an adverse karyotype. Despite frequent adverse-risk genetic changes, in our cohort mR172 cases had significantly improved overall survival vs non-mR172 cases (P = .01), and we validated that mR172 was associated with improved survival in an independent large data set. CONCLUSIONS: We show that MNs with mR172 represent a morphologically and phenotypically distinct subtype, which in our cohort exhibited relatively favorable survival that is not captured in current AML risk assignment.
Assuntos
Isocitrato Desidrogenase , Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Humanos , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , Estudos RetrospectivosRESUMO
Tumor mutational burden (TMB) refers to the number of somatic mutations in a tumor per megabase and is a biomarker for response to immune checkpoint inhibitor therapy. Immune checkpoint inhibitors are currently approved for tumors with TMB greater than or equal to 10 mutations/megabase. Many laboratories are currently reporting TMB values based upon targeted resequencing panels with limited genomic coverage. Due to sampling variation, this leads to significant uncertainty in the assay's TMB result, particularly at relatively low TMB levels near the 10 mutation per megabase therapeutic threshold. In order to allow clinicians and laboratorians to explore this uncertainty, we built a novel web application that allows a user to view the potential error of a TMB result given the sequencing panel size. This application also allows the user to explore the effect of incorporating knowledge of a specific tumor type's typical TMB distribution on the error profile of the TMB result.
Assuntos
Biomarcadores Tumorais , Neoplasias , Biomarcadores Tumorais/genética , Humanos , Inibidores de Checkpoint Imunológico , Mutação , Neoplasias/genética , Neoplasias/patologiaRESUMO
CONTEXT.: Quantification and detection of the t(9;22) (BCR-ABL1) translocation in chronic myelogenous leukemia and B-lymphoblastic leukemia are important for directing treatment protocols and monitoring disease relapse. However, quantification using traditional reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) is dependent on a calibration curve and is prone to laboratory-to-laboratory variation. Droplet digital polymerase chain reaction (ddPCR) is a novel method that allows for highly sensitive absolute quantification of transcript copy number. As such, ddPCR is a good candidate for disease monitoring, an assay requiring reproducible measurements with high specificity and sensitivity. OBJECTIVE.: To compare results of ddPCR and RT-qPCR BCR-ABL1 fusion transcript measurements of patient samples and determine if either method is superior. DESIGN.: We optimized and standardized a 1-step multiplexed ddPCR assay to detect BCR-ABL1 p190 and ABL1 e10 transcripts. The ddPCR optimization included varying cycle number and primer concentration with standardization of droplet generation and droplet number and analyses to improve data sensitivity. Following optimization, ddPCR measurements were performed on clinical samples and compared with traditional RT-qPCR results. RESULTS.: Droplet digital polymerase chain reaction was able to detect the BCR-ABL1 p190 transcript to 0.001% (1:10-5) with a calculated limit of detection and limit of quantitation of 4.1 and 5.3 transcripts, respectively. When tested on patient samples, ddPCR was able to identify 20% more positives than a laboratory-developed 2-step RT-qPCR assay. CONCLUSIONS.: Droplet digital polymerase chain reaction demonstrated increased detection of BCR-ABL1 compared with RT-qPCR. Improved detection of BCR-ABL1 p190 and the potential for improved standardization across multiple laboratories makes ddPCR a suitable method for disease monitoring in patients with acute B-lymphoblastic leukemia.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Translocação GenéticaRESUMO
BACKGROUND: Mu heavy chain disease is a rare lymphoid neoplasm characterized by vacuolated bone marrow plasma cells and secretion of defective mu immunoglobulin heavy chains. The biological basis of mu heavy chain disease is poorly understood. CASE PRESENTATION: We report a case of mu heavy chain disease with MYD88 L265P mutation and deletion of 6q, genetic aberrations that are both strongly associated with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Identification of the truncated mu immunoglobulin was facilitated by mass spectrometric analysis of the patient's serum. CONCLUSIONS: Mu heavy chain disease has been described as similar to chronic lymphocytic leukemia; however, the frequency of lymphocytosis in mu heavy chain disease has not been previously reported. We reviewed all previously published mu heavy chain disease reports and found that lymphocytosis is uncommon in the entity. This finding, along with the emerging genetic feature of recurrent MYD88 mutation in mu heavy chain disease, argues that at least a significant subset of cases are more similar to lymphoplasmacytic lymphoma than to chronic lymphocytic leukemia.
Assuntos
Doença das Cadeias Pesadas , Leucemia Linfocítica Crônica de Células B , Linfocitose , Linfoma , Macroglobulinemia de Waldenstrom , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Fator 88 de Diferenciação Mieloide/genética , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/patologiaRESUMO
Peripheral T-cell lymphomas (PTCL) are agressive lymphomas that develop from mature T cells. The most common PTCLs are genetically, molecularly, and clinically diverse and are generally associated with dismal outcomes. While Notch signaling plays a critically important role in both the development of immature T cells and their malignant transformation, its role in PTCL is poorly understood, despite the increasingly appreciated function of Notch in regulating the proliferation and differentiation of mature T cells. Here, we demonstrate that Notch receptors and their Delta-like family ligands (DLL1/DLL4) play a pathogenic role in PTCL. Notch1 activation was observed in common PTCL subtypes, including PTCL-not otherwise specified (NOS). In a large cohort of PTCL-NOS biopsies, Notch1 activation was significantly associated with surrogate markers of proliferation. Complementary genetically engineered mouse models and spontaneous PTCL models were used to functionally examine the role of Notch signaling, and Notch1/Notch2 blockade and pan-Notch blockade using dominant-negative MAML significantly impaired the proliferation of malignant T cells and PTCL progression in these models. Treatment with DLL1/DLL4 blocking antibodies established that Notch signaling is ligand-dependent. Together, these findings reveal a role for ligand-dependent Notch signaling in driving peripheral T-cell lymphomagenesis. SIGNIFICANCE: This work demonstrates that ligand-dependent Notch activation promotes the growth and proliferation of mature T-cell lymphomas, providing new therapeutic strategies for this group of aggressive lymphomas.