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3.
Nat Commun ; 9(1): 697, 2018 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-29449575

RESUMEN

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Daño del ADN , Epigénesis Genética , Leucemia Prolinfocítica de Células T/genética , Proteínas Proto-Oncogénicas/genética , Adulto , Anciano , Animales , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Línea Celular Tumoral , Femenino , Perfilación de la Expresión Génica/métodos , Células HEK293 , Humanos , Estimación de Kaplan-Meier , Leucemia Prolinfocítica de Células T/tratamiento farmacológico , Leucemia Prolinfocítica de Células T/metabolismo , Masculino , Ratones Transgénicos , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas/metabolismo
4.
Leukemia ; 32(3): 774-787, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28804127

RESUMEN

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.


Asunto(s)
Antineoplásicos/farmacología , Biomarcadores de Tumor , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Ensayos Analíticos de Alto Rendimiento , Leucemia Prolinfocítica de Células T/genética , Mutación , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Ciclo Celular/genética , Línea Celular Tumoral , Aberraciones Cromosómicas , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Quinasas Janus/metabolismo , Leucemia Prolinfocítica de Células T/tratamiento farmacológico , Leucemia Prolinfocítica de Células T/metabolismo , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Oxazoles/farmacología , Fenotipo , Inhibidores de Proteínas Quinasas/farmacología , Factores de Transcripción STAT/metabolismo , Tiazoles/farmacología
6.
Nat Commun ; 8: 15869, 2017 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-28635960

RESUMEN

Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8+ T-cell clones; in 20% (5/25) of patients CD8+ T cells, but not CD4+ T cells, harbour somatic mutations. In healthy controls (n=20), only one mutation is identified in the CD8+ T-cell pool. Mutations exist exclusively in the expanded CD8+ effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8+ T cells, which may have pathogenic significance for RA and other autoimmune diseases.


Asunto(s)
Artritis Reumatoide/genética , Mutación , Linfocitos T Citotóxicos/patología , Adulto , Factores de Edad , Anciano , Artritis Reumatoide/patología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/fisiología , Estudios de Casos y Controles , Femenino , Genes Codificadores de la Cadena beta de los Receptores de Linfocito T , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Factor 1 Regulador del Interferón/genética , Factor 1 Regulador del Interferón/inmunología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/fisiología
8.
Leukemia ; 31(5): 1108-1116, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-27890936

RESUMEN

Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naïve CD56bright NK cells had decreased relapse-free survival. In addition, the TNF-α/IFN-γ cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents.


Asunto(s)
Mesilato de Imatinib/uso terapéutico , Células Asesinas Naturales/citología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Estudios de Casos y Controles , Citocinas/metabolismo , Dasatinib/uso terapéutico , Supervivencia sin Enfermedad , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Recuento de Linfocitos , Subgrupos Linfocitarios/citología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Privación de Tratamiento
9.
Leukemia ; 30(9): 1853-60, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27133821

RESUMEN

Dasatinib (DAS) and interferon-α have antileukemic and immunostimulatory effects and induce deep responses in chronic myeloid leukemia (CML). We assigned 40 newly diagnosed chronic-phase CML patients to receive DAS 100 mg o.d. followed by addition of pegylated interferon-α2b (PegIFN) after 3 months (M3). The starting dose of PegIFN was 15 µg/week and it increased to 25 µg/week at M6 until M15. The combination was well tolerated with manageable toxicity. Of the patients, 84% remained on PegIFN at M12 and 91% (DAS) and 73% (PegIFN) of assigned dose was given. Only one patient had a pleural effusion during first year, and three more during the second year. After introduction of PegIFN we observed a steep increase in response rates. Major molecular response was achieved in 10%, 57%, 84% and 89% of patients at M3, M6, M12 and M18, respectively. At M12, MR(4) was achieved by 46% and MR(4.5) by 27% of patients. No patients progressed to advanced phase. In conclusion, the combination treatment appeared safe with very promising efficacy. A randomized comparison of DAS±PegIFN is warranted.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Dasatinib/administración & dosificación , Interferón-alfa/administración & dosificación , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Polietilenglicoles/administración & dosificación , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Derrame Pleural , Proteínas Recombinantes/administración & dosificación , Inducción de Remisión , Resultado del Tratamiento , Adulto Joven
12.
Blood Cancer J ; 5: e309, 2015 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-25933373

RESUMEN

Chronic myeloid leukemia in blast crisis (CML BC) remains a challenging disease to treat despite the introduction and advances in tyrosine kinase inhibitor (TKI) therapy. In this study we set out to identify novel candidate drugs for CML BC by using an unbiased high-throughput drug testing platform. We used three CML cell lines representing different types of CML blast phases (K562, EM-2 and MOLM-1) and primary leukemic cells from three CML BC patients. Profiling of drug responses was performed with a drug sensitivity and resistance testing platform comprising 295 anticancer agents. Overall, drug sensitivity scores and the drug response profiles of cell line and primary cell samples correlated well and were distinct from other types of leukemia samples. The cell lines were highly sensitive to TKIs and the clinically TKI-resistant patient samples were also resistant ex vivo. Comparison of cell line and patient sample data identified new candidate drugs for CML BC, such as vascular endothelial growth factor receptor and nicotinamide phosphoribosyltransferase inhibitors. Our results indicate that these drugs in particular warrant further evaluation by analyzing a larger set of primary patient samples. The results also pave way for designing rational combination therapies.


Asunto(s)
Antineoplásicos/farmacología , Crisis Blástica/tratamiento farmacológico , Supervivencia Celular/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Adulto , Línea Celular Tumoral , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Ensayos Analíticos de Alto Rendimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología
13.
Leukemia ; 29(4): 886-94, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25306898

RESUMEN

Failure to undergo activation-induced cell death due to global dysregulation of apoptosis is the pathogenic hallmark of large granular lymphocyte (LGL) leukemia. Consequently, immunosuppressive agents are rational choices for treatment. This first prospective trial in LGL leukemia was a multicenter, phase 2 clinical trial evaluating methotrexate (MTX) at 10 mg/m(2) orally weekly as initial therapy (step 1). Patients failing MTX were eligible for treatment with cyclophosphamide at 100 mg orally daily (step 2). The overall response in step 1 was 38% with 95% confidence interval (CI): 26 and 53%. The overall response in step 2 was 64% with 95% CI: 35 and 87%. The median overall survival for patients with anemia was 69 months with a 95% CI lower bound of 46 months and an upper bound not yet reached. The median overall survival for patients with neutropenia has not been reached 13 years from study activation. Serum biomarker studies confirmed the inflammatory milieu of LGL but were not a priori predictive of response. We identify a gene expression signature that correlates with response and may be STAT3 mutation driven. Immunosuppressive therapies have efficacy in LGL leukemia. Gene signature and mutational profiling may be an effective tool in determining whether MTX is an appropriate therapy.


Asunto(s)
Anemia/tratamiento farmacológico , Regulación Leucémica de la Expresión Génica , Inmunosupresores/uso terapéutico , Leucemia Linfocítica Granular Grande/tratamiento farmacológico , Metotrexato/uso terapéutico , Neutropenia/tratamiento farmacológico , Factor de Transcripción STAT3/genética , Anciano , Anciano de 80 o más Años , Anemia/complicaciones , Anemia/genética , Anemia/mortalidad , Ciclofosfamida/uso terapéutico , Monitoreo de Drogas , Femenino , Finlandia , Humanos , Cooperación Internacional , Leucemia Linfocítica Granular Grande/complicaciones , Leucemia Linfocítica Granular Grande/genética , Leucemia Linfocítica Granular Grande/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Neutropenia/complicaciones , Neutropenia/genética , Neutropenia/mortalidad , Factor de Transcripción STAT3/metabolismo , Análisis de Supervivencia , Transcriptoma , Estados Unidos
15.
Blood Cancer J ; 3: e168, 2013 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-24317090

RESUMEN

T-cell large granular lymphocytic (T-LGL) leukemia is a clonal disease characterized by the expansion of mature CD3+CD8+ cytotoxic T cells. It is often associated with autoimmune disorders and immune-mediated cytopenias. Our recent findings suggest that up to 40% of T-LGL patients harbor mutations in the STAT3 gene, whereas STAT5 mutations are present in 2% of patients. In order to identify putative disease-causing genetic alterations in the remaining T-LGL patients, we performed exome sequencing from three STAT mutation-negative patients and validated the findings in 113 large granular lymphocytic (LGL) leukemia patients. On average, 11 CD8+ LGL leukemia cell-specific high-confidence nonsynonymous somatic mutations were discovered in each patient. Interestingly, all patients had at least one mutation that affects either directly the STAT3-pathway (such as PTPRT) or T-cell activation (BCL11B, SLIT2 and NRP1). In all three patients, the STAT3 pathway was activated when studied by RNA expression or pSTAT3 analysis. Screening of the remaining 113 LGL leukemia patients did not reveal additional patients with same mutations. These novel mutations are potentially biologically relevant and represent rare genetic triggers for T-LGL leukemia, and are associated with similar disease phenotype as observed in patients with mutations in the STAT3 gene.

16.
Leukemia ; 27(7): 1520-6, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23328954

RESUMEN

Chronic myeloid leukemia (CML) stem cells appear resistant to tyrosine kinase inhibitors (TKIs) in vitro, but their impact and drug sensitivity in vivo has not been systematically assessed. We prospectively analyzed the proportion of Philadelphia chromosome-positive leukemic stem cells (LSCs, Ph+CD34+CD38-) and progenitor cells (LPCs, Ph+CD34+CD38+) from 46 newly diagnosed CML patients both at the diagnosis and during imatinib or dasatinib therapy (ClinicalTrials.gov NCT00852566). At diagnosis, the proportion of LSCs varied markedly (1-100%) between individual patients with a significantly lower median value as compared with LPCs (79% vs 96%, respectively, P=0.0001). The LSC burden correlated with leukocyte count, spleen size, hemoglobin and blast percentage. A low initial LSC percentage was associated with less therapy-related hematological toxicity and superior cytogenetic and molecular responses. After initiation of TKI therapy, the LPCs and LSCs rapidly decreased in both therapy groups, but at 3 months time point the median LPC level was significantly lower in dasatinib group compared with imatinib patients (0.05% vs 0.68%, P=0.032). These data detail for the first time the prognostic significance of the LSC burden at diagnosis and show that in contrast to in vitro data, TKI therapy rapidly eradicates the majority of LSCs in patients.


Asunto(s)
Benzamidas/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Células Madre Neoplásicas/patología , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Tiazoles/uso terapéutico , Adulto , Anciano , Antineoplásicos/uso terapéutico , Dasatinib , Femenino , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Persona de Mediana Edad , Proyectos Piloto , Valor Predictivo de las Pruebas , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del Tratamiento
17.
Leukemia ; 27(4): 914-24, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23192016

RESUMEN

Tyrosine kinase inhibitors (TKIs) have potent effects on malignant cells, and they also target kinases in normal cells, which may have therapeutic implications. Using a collection of 55 leukemia patients treated with TKI therapy (chronic myeloid leukemia, n=47; acute lymphoblastic leukemia, n=8), we found that dasatinib, a second-generation broad-spectrum TKI, induced a rapid, dose-dependent and substantial mobilization of non-leukemic lymphocytes and monocytes in blood peaking 1-2 h after an oral intake and the blood counts closely mirrored drug plasma concentration. A preferential mobilization was observed for natural killer (NK), NK T, B and γδ+ T cells. Mobilization was coupled with a more effective transmigration of leukocytes through an endothelial cell layer and improved cytotoxicity of NK cells. Platelet numbers decreased markedly after the drug intake in a proportion of patients. Similar effects on blood cell dynamics and function were not observed with any other TKI (imatinib, nilotinib and bosutinib). Thus, dasatinib induces a unique, rapid mobilization and activation of cytotoxic, extravasation-competent lymphocytes, which may not only enhance antileukemia immune responses but can also be causally related to the side-effect profile of the drug (pleural effusions, thrombocytopenia).


Asunto(s)
Antineoplásicos/farmacología , Pirimidinas/farmacología , Linfocitos T Citotóxicos/efectos de los fármacos , Tiazoles/farmacología , Adulto , Citocinas/genética , Dasatinib , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Células K562 , Masculino , Linfocitos T Citotóxicos/inmunología
19.
Leukemia ; 25(10): 1587-97, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21647156

RESUMEN

The tyrosine kinase inhibitor dasatinib exerts immunosuppressive effects on T-cells and NK-cells in vitro. However, in some dasatinib-treated leukemia patients, clonal lymphocytosis with large granular lymphocyte (LGL) morphology develops, and this is associated with enhanced therapeutic responses. To elucidate the mechanistic basis for this paradoxical observation, we conducted detailed phenotypic and functional analyses of T-cell and NK-cell populations from 25 dasatinib-treated leukemia patients. All tested patients with LGL expansions (15/16) were cytomegalovirus (CMV) immunoglobulin (IgG) seropositive with high frequencies of CMV-specific CD8(+) T-cells; 5/16 LGL patients also experienced symptomatic CMV reactivation during dasatinib therapy. Expanded T-cell and NK-cell populations exhibited late differentiated (CD27(-)CD57(+)) phenotypes; this was associated with a predisposition to apoptosis within the T-cell compartment and impaired NK-cell cytotoxicity. Only 3/9 non-LGL patients were CMV IgG seropositive. Dasatinib inhibited in vitro lymphocyte functions, similarly in LGL patients and controls. Notably, distinct CD8(high) and CD8(low) T-cell subsets were observed in LGL patients; this phenotypic dichotomy was also apparent in CMV-specific CD8(+) T-cell populations, and exhibited features consistent with antigen-driven activation. In addition, plasma levels of IP-10, IL-6, monokine induced by interferon-γ and interleukin-2R were significantly increased in LGL patients. These data provide evidence that dasatinib-associated LGL expansion is linked to CMV reactivation and suggest a potential mechanism for this phenomenon.


Asunto(s)
Linfocitos T CD8-positivos/citología , Diferenciación Celular , División Celular , Citomegalovirus/fisiología , Células Asesinas Naturales/citología , Leucemia/inducido químicamente , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Tiazoles/efectos adversos , Activación Viral , Adulto , Anciano , Apoptosis , Secuencia de Bases , Cartilla de ADN , Dasatinib , Femenino , Citometría de Flujo , Humanos , Leucemia/inmunología , Leucemia/patología , Leucemia/virología , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
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