RESUMEN
Dysregulation of apoptotic machinery is one mechanism by which acute myeloid leukemia (AML) acquires a clonal survival advantage. B-cell lymphoma protein-2 (BCL2) overexpression is a common feature in hematologic malignancies. The selective BCL2 inhibitor, venetoclax (VEN) is used in combination with azacitidine (AZA), a DNAmethyltransferase inhibitor (DNMTi), to treat patients with AML. Despite promising response rates to VEN/AZA, resistance to the agent is common. One identified mechanism of resistance is the upregulation of myeloid cell leukemia-1 protein (MCL1). Pevonedistat (PEV), a novel agent that inhibits NEDD8-activating enzyme, and AZA both upregulate NOXA (PMAIP1), a BCL2 family protein that competes with effector molecules at the BH3 binding site of MCL1. We demonstrate that PEV/AZA combination induces NOXA to a greater degree than either PEV or AZA alone, which enhances VEN-mediated apoptosis. Herein, using AML cell lines and primary AML patient samples ex vivo, including in cells with genetic alterations linked to treatment resistance, we demonstrate robust activity of the PEV/VEN/AZA triplet. These findings were corroborated in preclinical systemic engrafted models of AML. Collectively, these results provide rational for combining PEV/VEN/AZA as a novel therapeutic approach in overcoming AML resistance in current therapies.
Asunto(s)
Azacitidina , Leucemia Mieloide Aguda , Azacitidina/farmacología , Azacitidina/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Ciclopentanos , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Pirimidinas , SulfonamidasRESUMEN
OBJECTIVE: Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C. DESIGN: 70 treatment-naive patients were randomised to 4 weeks of ribavirin (1000-1200 mg/d) or none, followed by PEG-IFNα-2a and ribavirin at standard doses and durations. Patients were also randomised to a liver biopsy 24 h before or 6 h after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10. RESULTS: After 4 weeks of ribavirin monotherapy, hepatitis C virus (HCV) levels decreased by 0.5±0.5 log10 (p=0.009 vs controls) and ALT by 33% (p<0.001). Ribavirin pretreatment, while modestly augmenting ISG induction by PEG-IFN, did not modify the virological response to subsequent PEG-IFN and ribavirin treatment. However, biochemical, but not virological, response to ribavirin monotherapy predicted response to subsequent combination treatment (rapid virological response, 71% in biochemical responders vs 22% non-responders, p=0.01; early virological response, 100% vs 68%, p=0.03; sustained virological response 83% vs 41%, p=0.053). Ribavirin monotherapy lowered serum IP-10 levels but had no effect on ISG expression in PBMC. CONCLUSIONS: Ribavirin is a weak antiviral but its clinical effect seems to be mediated by a separate, indirect mechanism, which may act to reset IFN-responsiveness in HCV-infected liver.
Asunto(s)
Antivirales/farmacología , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/farmacología , Hígado/efectos de los fármacos , Polietilenglicoles/farmacología , Ribavirina/farmacología , Transcriptoma/efectos de los fármacos , Carga Viral/efectos de los fármacos , Adulto , Antivirales/uso terapéutico , Biomarcadores/metabolismo , Esquema de Medicación , Quimioterapia Combinada , Femenino , Perfilación de la Expresión Génica , Hepatitis C Crónica/genética , Hepatitis C Crónica/virología , Humanos , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Interferón-alfa/uso terapéutico , Hígado/metabolismo , Hígado/virología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Polietilenglicoles/uso terapéutico , Estudios Prospectivos , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Ribavirina/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Mathematical modeling of hepatitis C virus (HCV) kinetics indicated that cellular immune responses contribute to interferon (IFN)-induced clearance of HCV. We investigated a potential role of natural killer (NK) cells in this process. METHODS: Phenotype and function of blood and liver NK cells were studied during the first 12 weeks of treatment with pegylated IFN-alfa and ribavirin, the time period used to define the early virological response. RESULTS: Within hours of treatment initiation, NK cells of patients that had an early virological response increased expression of activating receptors NKG2D, NKp30, and CD16 and decreased expression of NKG2C and 2B4, along with inhibitory receptors SIGLEC7 and NKG2A, resulting in NK cell activation. NK cell cytotoxicity, measured by degranulation and tumor necrosis factor-related apoptosis-inducing ligand production, peaked after 24 hours (P<.01), concomitant with an increase in alanine aminotransferase levels (P<.05), whereas IFN-γ production decreased within 6 hours and did not recover for more than 4 weeks (P<.05). NK cells from liver biopsies taken 6 hours after treatment initiation had increased numbers of cytotoxic CD16+NK cells (P<.05) and a trend toward increased production of tumor necrosis factor-related apoptosis-inducing ligand. Degranulation of peripheral blood NK cells correlated with treatment-induced, first-phase decreases in viral load (P<.05) and remained higher in early virological responders than in nonresponders for weeks. CONCLUSIONS: IFN activates NK cells early after treatment is initiated. Their cytotoxic function, in particular, is strongly induced, which correlates to virologic response. Therefore, NK cell activation indicates responsiveness to IFN-α-based treatment and suggests the involvement of the innate immune cells in viral clearance.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C/tratamiento farmacológico , Inmunidad Innata/efectos de los fármacos , Interferón-alfa/uso terapéutico , Células Asesinas Naturales/efectos de los fármacos , Hígado/efectos de los fármacos , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Adulto , Alanina Transaminasa/sangre , Antígenos de Diferenciación Mielomonocítica/metabolismo , Biopsia , Degranulación de la Célula/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Quimioterapia Combinada , Femenino , Hepacivirus/genética , Hepatitis C/diagnóstico , Hepatitis C/inmunología , Humanos , Interferón gamma/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/virología , Lectinas/metabolismo , Hígado/inmunología , Hígado/virología , Masculino , Maryland , Persona de Mediana Edad , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismo , ARN Viral/sangre , Proteínas Recombinantes/uso terapéutico , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Carga ViralRESUMEN
Ageing of haematopoietic stem cells (HSCs) contributes to deficits in the aged haematopoietic system. HSC decline is driven in part by DNA damage accumulation; yet, how ageing impacts the acute DNA damage response (DDR) of HSCs is poorly understood. We show that old HSCs exhibit diminished ATM activity and attenuated DDR, leading to elevated clonal survival in response to a range of genotoxins that was underwritten by diminished apoptotic priming. Distinct HSC subsets exhibited ageing-dependent and subtype-dependent differences in apoptotic priming and survival in response to DNA damage. The defective DDR of old HSCs was non-cell autonomous, as ATM signalling and clonal survival in response to DNA damage could be restored to levels observed in young HSCs post-transplantated into young recipients. These data indicate that defective DDR and diminished apoptotic priming provide a selective advantage to old HSCs that may contribute to mutation accrual and disease predisposition.
Asunto(s)
Apoptosis , Senescencia Celular , Daño del ADN , Reparación del ADN , Células Madre Hematopoyéticas/enzimología , Factores de Edad , Animales , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Células Cultivadas , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/patología , Masculino , Ratones Endogámicos C57BL , Transducción de Señal , Factores de TiempoRESUMEN
Suppression of apoptosis by expression of antiapoptotic BCL2 family members is a hallmark of acute myeloblastic leukemia (AML). Induced myeloid leukemia cell differentiation protein (MCL1), an antiapoptotic BCL2 family member, is commonly upregulated in AML cells and is often a primary mode of resistance to treatment with the BCL2 inhibitor venetoclax. Here, we describe VU661013, a novel, potent, selective MCL1 inhibitor that destabilizes BIM/MCL1 association, leads to apoptosis in AML, and is active in venetoclax-resistant cells and patient-derived xenografts. In addition, VU661013 was safely combined with venetoclax for synergy in murine models of AML. Importantly, BH3 profiling of patient samples and drug-sensitivity testing ex vivo accurately predicted cellular responses to selective inhibitors of MCL1 or BCL2 and showed benefit of the combination. Taken together, these data suggest a strategy of rationally using BCL2 and MCL1 inhibitors in sequence or in combination in AML clinical trials. SIGNIFICANCE: Targeting antiapoptotic proteins in AML is a key therapeutic strategy, and MCL1 is a critical antiapoptotic oncoprotein. Armed with novel MCL1 inhibitors and the potent BCL2 inhibitor venetoclax, it may be possible to selectively induce apoptosis by combining or thoughtfully sequencing these inhibitors based on a rational evaluation of AML.See related commentary by Leber et al., p. 1511.This article is highlighted in the In This Issue feature, p. 1494.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Indoles/farmacología , Leucemia Mieloide/tratamiento farmacológico , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Pirazinas/farmacología , Pirazoles/farmacología , Sulfonamidas/farmacología , Enfermedad Aguda , Animales , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Sinergismo Farmacológico , Células HL-60 , Humanos , Indoles/química , Células K562 , Leucemia Mieloide/metabolismo , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Pirazinas/química , Pirazoles/química , Células THP-1 , Células U937 , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Numerous variant alleles are associated with human acute myeloid leukemia (AML). However, the same variants are also found in individuals with no hematological disease, making their functional relevance obscure. Through NOD.Cg-PrkdcscidIl2rgtmlWjl/Sz (NSG) xenotransplantation, we functionally identified preleukemic and leukemic stem cell populations present in FMS-like tyrosine kinase 3 internal tandem duplication-positive (FLT3-ITD)+ AML patient samples. By single-cell DNA sequencing, we identified clonal structures and linked mutations with in vivo fates, distinguishing mutations permissive of nonmalignant multilineage hematopoiesis from leukemogenic mutations. Although multiple somatic mutations coexisted at the single-cell level, inhibition of the mutation strongly associated with preleukemic to leukemic stem cell transition eliminated AML in vivo. Moreover, concurrent inhibition of BCL-2 (B cell lymphoma 2) uncovered a critical dependence of resistant AML cells on antiapoptotic pathways. Co-inhibition of pathways critical for oncogenesis and survival may be an effective strategy that overcomes genetic diversity in human malignancies. This approach incorporating single-cell genomics with the NSG patient-derived xenograft model may serve as a broadly applicable resource for precision target identification and drug discovery.
Asunto(s)
Leucemia Mieloide Aguda/genética , Mutación/genética , Transducción de Señal/genética , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Carcinogénesis/genética , Carcinogénesis/patología , Células Clonales , Femenino , Genómica , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Análisis de Secuencia de ADN , Análisis de la Célula Individual , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with dismal outcomes for which no standard therapy exists. We found that primary BPDCN cells were dependent on the antiapoptotic protein BCL2 and were uniformly sensitive to the BCL2 inhibitor venetoclax, as measured by direct cytotoxicity, apoptosis assays, and dynamic BH3 profiling. Animals bearing BPDCN patient-derived xenografts had disease responses and improved survival after venetoclax treatment in vivo Finally, we report on 2 patients with relapsed/refractory BPDCN who received venetoclax off-label and experienced significant disease responses. We propose that venetoclax or other BCL2 inhibitors undergo expedited clinical evaluation in BPDCN, alone or in combination with other therapies. In addition, these data illustrate an example of precision medicine to predict treatment response using ex vivo functional assessment of primary tumor tissue, without requiring a genetic biomarker. SIGNIFICANCE: Therapy for BPDCN is inadequate, and survival in patients with the disease is poor. We used primary tumor cell functional profiling to predict BCL2 antagonist sensitivity as a common feature of BPDCN, and demonstrated in vivo clinical activity of venetoclax in patient-derived xenografts and in 2 patients with relapsed chemotherapy-refractory disease. Cancer Discov; 7(2); 156-64. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 115.
Asunto(s)
Antineoplásicos/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Células Dendríticas/patología , Neoplasias Hematológicas/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Sulfonamidas/administración & dosificación , Anciano , Anciano de 80 o más Años , Animales , Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Dendríticas/metabolismo , Neoplasias Hematológicas/metabolismo , Humanos , Masculino , Ratones , Medicina de Precisión , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Sulfonamidas/farmacología , Análisis de Supervivencia , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that when overexpressed is associated with high tumor grade, poor survival, and resistance to chemotherapy. Mcl-1 is amplified in many human cancers, and knockdown of Mcl-1 using RNAi can lead to apoptosis. Thus, Mcl-1 is a promising cancer target. Here, we describe the discovery of picomolar Mcl-1 inhibitors that cause caspase activation, mitochondrial depolarization, and selective growth inhibition. These compounds represent valuable tools to study the role of Mcl-1 in cancer and serve as useful starting points for the discovery of clinically useful Mcl-1 inhibitors. PDB ID CODES: Comp. 2: 5IEZ; Comp. 5: 5IF4.
Asunto(s)
Antineoplásicos/farmacología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Animales , Antineoplásicos/química , Proteína 11 Similar a Bcl2/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Descubrimiento de Drogas , Humanos , Inmunoprecipitación , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteína bcl-X/metabolismoRESUMEN
Upfront resistance to chemotherapy and relapse following remission are critical problems in leukemia that are generally attributed to subpopulations of chemoresistant tumor cells. There are, however, limited means for prospectively identifying these subpopulations, which hinders an understanding of therapeutic resistance. BH3 profiling is a functional single-cell analysis using synthetic BCL-2 BH3 domain-like peptides that measures mitochondrial apoptotic sensitivity or "priming." Here, we observed that the extent of apoptotic priming is heterogeneous within multiple cancer cell lines and is not the result of experimental noise. Apoptotic priming was also heterogeneous in treatment-naive primary human acute myeloid leukemia (AML) myeloblasts, and this heterogeneity decreased in chemotherapy-treated AML patients. The priming of the most apoptosis-resistant tumor cells, rather than the median priming of the population, best predicted patient response to induction chemotherapy. For several patients, these poorly primed subpopulations of AML tumor cells were enriched for antiapoptotic proteins. Developing techniques to identify and understand these apoptosis-insensitive subpopulations of tumor cells may yield insights into clinical chemoresistance and potentially improve therapeutic outcomes in AML.
Asunto(s)
Apoptosis/efectos de los fármacos , Leucemia Mieloide Aguda/patología , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Etopósido/farmacología , Células Precursoras de Granulocitos/efectos de los fármacos , Células Precursoras de Granulocitos/fisiología , Humanos , Concentración 50 Inhibidora , Leucemia Mieloide Aguda/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Análisis de la Célula IndividualRESUMEN
We present a phase II, single-arm study evaluating 800 mg daily venetoclax, a highly selective, oral small-molecule B-cell leukemia/lymphoma-2 (BCL2) inhibitor in patients with high-risk relapsed/refractory acute myelogenous leukemia (AML) or unfit for intensive chemotherapy. Responses were evaluated following revised International Working Group (IWG) criteria. The overall response rate was 19%; an additional 19% of patients demonstrated antileukemic activity not meeting IWG criteria (partial bone marrow response and incomplete hematologic recovery). Twelve (38%) patients had isocitrate dehydrogenase 1/2 mutations, of whom 4 (33%) achieved complete response or complete response with incomplete blood count recovery. Six (19%) patients had BCL2-sensitive protein index at screening, which correlated with time on study. BH3 profiling was consistent with on-target BCL2 inhibition and identified potential resistance mechanisms. Common adverse events included nausea, diarrhea and vomiting (all grades), and febrile neutropenia and hypokalemia (grade 3/4). Venetoclax demonstrated activity and acceptable tolerability in patients with AML and adverse features. SIGNIFICANCE: Venetoclax monotherapy demonstrated clinical activity in patients with AML (relapsed/refractory or unfit for intensive chemotherapy) with a tolerable safety profile in this phase II study. Predictive markers of response consistent with BCL2 dependence were identified. Clinical and preclinical findings provide a compelling rationale to evaluate venetoclax combined with other agents in AML. Cancer Discov; 6(10); 1106-17. ©2016 AACRSee related commentary by Pullarkat and Newman, p. 1082This article is highlighted in the In This Issue feature, p. 1069.
Asunto(s)
Antineoplásicos/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sulfonamidas/efectos adversos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Targeted therapies designed to exploit specific molecular pathways in aggressive cancers are an exciting area of current research. Mixed Lineage Leukemia (MLL) mutations such as the t(4;11) translocation cause aggressive leukemias that are refractory to conventional treatment. The t(4;11) translocation produces an MLL/AF4 fusion protein that activates key target genes through both epigenetic and transcriptional elongation mechanisms. In this study, we show that t(4;11) patient cells express high levels of BCL-2 and are highly sensitive to treatment with the BCL-2-specific BH3 mimetic ABT-199. We demonstrate that MLL/AF4 specifically upregulates the BCL-2 gene but not other BCL-2 family members via DOT1L-mediated H3K79me2/3. We use this information to show that a t(4;11) cell line is sensitive to a combination of ABT-199 and DOT1L inhibitors. In addition, ABT-199 synergizes with standard induction-type therapy in a xenotransplant model, advocating for the introduction of ABT-199 into therapeutic regimens for MLL-rearranged leukemias.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Sulfonamidas/farmacología , Animales , Línea Celular Tumoral , Genes bcl-2 , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Metilación , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. Here, we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC50 was approximately 10 nmol/L, and cell death occurred within 2 hours. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia, a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profiling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on-target mitochondrial mechanism of action. Our protein and BH3 profiling studies provide promising tools that can be tested as predictive biomarkers in any clinical trial of ABT-199 in AML.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Fragmentos de Péptidos/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Sulfonamidas/farmacología , Compuestos de Anilina/farmacología , Animales , Biomarcadores de Tumor , Compuestos de Bifenilo/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Leucémica de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/patología , Ratones , Mitocondrias/metabolismo , Neoplasias Experimentales , Nitrofenoles/farmacología , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Leukemia stem cells (LSCs) are likely to be the source for both therapeutic resistance and relapse in myeloid malignancies. As reported in this issue of Cell Stem Cell, Lagadinou et al. (2013) and Goff et al. (2013) support selective targeting of LSCs by small molecule antagonists of anti-apoptotic BCL-2 family proteins.
Asunto(s)
Leucemia Mieloide Aguda/metabolismo , Leucemia/patología , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , HumanosRESUMEN
Among many species of insects, females gain fitness benefits by producing numerous offspring. Yet actions related to producing numerous offspring such as mating with multiple males, producing oocytes and placing offspring in sub-optimal environments incur costs. Females can decrease the magnitude of these costs by retaining gametes when suitable oviposition sites are absent. We used the pomace fly, Drosophila melanogaster, to explore how the availability of fresh feeding/oviposition medium influenced female fitness via changes in offspring survivorship and the modulation of gamete release. Availability of fresh medium affected the absolute number and temporal production of offspring. This outcome was attributable to both decreased larval survival under crowded conditions and to female modulation of gamete release. Direct examination of the number of sperm retained among the different female storage organs revealed that females 'hold on' to sperm, retaining more sperm in storage, disproportionately within the spermathecae, when exposed infrequently to fresh medium. Despite this retention, females with lower rates of storage depletion exhibited decreased sperm use efficiency shortly after mating. This study provides direct evidence that females influence the rate of sperm depletion from specific storage sites in a way that can affect both female and male fitness. The possible adaptive significance of selective gamete utilization by female Drosophila includes lowering costs associated with frequent remating and larval overcrowding when oviposition sites are limiting, as well as potentially influencing paternity when females store sperm from multiple males.
Asunto(s)
Drosophila melanogaster/fisiología , Genitales Femeninos/fisiología , Oviposición/fisiología , Conducta Sexual Animal/fisiología , Espermatozoides/fisiología , Animales , Femenino , Aptitud Genética/fisiología , Genitales Femeninos/anatomía & histología , Masculino , Densidad de PoblaciónRESUMEN
Antigen-specific T cells can be induced by direct priming and cross-priming. To investigate cross-priming as a vaccination approach dendritic cells were transfected with cytopathogenic viral RNA-replicons that expressed domains of the tumor-associated Her2-antigen and injected into MHC-discordant mice that did not allow direct priming. Upon tumor challenge 75% of the vaccinated, but none of the mock-vaccinated mice remained tumor-free. The anti-tumor effect required T cells and correlated with the vigor of the cross-primed CD8 T cell response. Her2-specific antibodies were not detected. This study highlights the potential of T cell cross-priming in cancer immunotherapy.