RESUMEN
Acute myeloid leukemia (AML) is a genetically heterogeneous disease, in that a multitude of oncogenic drivers and chromosomal abnormalities have been identified and associated with the leukemic transformation of myeloid blasts. However, little is known as to how individual mutations influence the interaction between the immune system and AML cells and the efficacy of the immune system in AML disease control. In this review, we will discuss how AML cells potentially activate the immune system and what evidence there is to support the role of the immune system in controlling this disease. We will specifically examine the importance of antigen presentation in fostering an effective anti-AML immune response, explore the disruption of immune responses during AML disease progression, and discuss the emerging role of the oncoprotein MYC in driving immune suppression in AML.
RESUMEN
Epigenetic modifications, particularly through methylation of DNA packaging histones, play a pivotal role in controlling gene expression. Aberrant patterns of histone methylation have been associated with the development and progression of hematological malignancies. Unraveling the impact of aberrant histone marks on gene expression and leukemogenesis has spurred a concerted effort to develop clinically effective epigenetic therapies. In malignancies associated with the accumulation of histone H3 lysine trimethylation (H3K27me3), one such intervention involves preventing the deposition of this repressive histone mark by inhibiting the histone-modifying enzymes EZH1 and EZH2. While inhibition of EZH1/2 has demonstrated efficacy in both preclinical studies and clinical trials in various cancers, studies delineating the dynamic effect of EZH1/2 inhibition on H3K27me3 and disease relapse in clinical samples are lacking. In a recent publication, Yamagishi et al. explore how responses of a patient with adult T-cell leukemia/lymphoma to valemetostat, an EZH1/2 inhibitor, are associated with changes in H3K27me3, chromatin accessibility and gene expression, and how these changes can be circumvented in relapsed disease.
Asunto(s)
Epigénesis Genética , Histonas , Leucemia-Linfoma de Células T del Adulto , Animales , Humanos , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Histonas/metabolismo , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/patología , Complejo Represivo Polycomb 2/metabolismo , Complejo Represivo Polycomb 2/genéticaRESUMEN
Acute myeloid leukemia (AML) is a genetically heterogeneous, aggressive hematological malignancy induced by distinct oncogenic driver mutations. The effect of specific AML oncogenes on immune activation or suppression is unclear. Here, we examine immune responses in genetically distinct models of AML and demonstrate that specific AML oncogenes dictate immunogenicity, the quality of immune response and immune escape through immunoediting. Specifically, expression of NrasG12D alone is sufficient to drive a potent anti-leukemia response through increased MHC Class II expression that can be overcome with increased expression of Myc. These data have important implications for the design and implementation of personalized immunotherapies for patients with AML.
Asunto(s)
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/patología , Oncogenes , Neoplasias Hematológicas/genéticaRESUMEN
Murine models offer a valuable tool to recapitulate genetically defined subtypes of AML, and to assess the potential of compound mutations and clonal evolution during disease progression. This is of particular importance for difficult to treat leukemias such as FLT3 internal tandem duplication (ITD) positive AML. While conditional gene targeting by Cre recombinase is a powerful technology that has revolutionized biomedical research, consequences of Cre expression such as lack of fidelity, toxicity or off-target effects need to be taken into consideration. We report on a transgenic murine model of FLT3-ITD induced disease, where Cre recombinase expression alone, and in the absence of a conditional allele, gives rise to an aggressive leukemia phenotype. Here, expression of various Cre recombinases leads to polyclonal expansion of FLT3ITD/ITD progenitor cells, induction of a differentiation block and activation of Myc-dependent gene expression programs. Our report is intended to alert the scientific community of potential risks associated with using this specific mouse model and of unexpected effects of Cre expression when investigating cooperative oncogenic mutations in murine models of cancer.
Asunto(s)
Leucemia Mieloide Aguda , Animales , Ratones , Modelos Animales de Enfermedad , Tirosina Quinasa 3 Similar a fms/genética , Duplicación de Gen , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Ratones Transgénicos , MutaciónRESUMEN
Chemotherapy-resistant acute myeloid leukemia (AML), frequently driven by clonal evolution, has a dismal prognosis. A genome-wide CRISPR knockout screen investigating resistance to doxorubicin and cytarabine (Dox/AraC) in human AML cell lines identified gene knockouts involving AraC metabolism and genes that regulate cell cycle arrest (cyclin dependent kinase inhibitor 2A (CDKN2A), checkpoint kinase 2 (CHEK2) and TP53) as contributing to resistance. In human AML cohorts, reduced expression of CDKN2A conferred inferior overall survival and CDKN2A downregulation occurred at relapse in paired diagnosis-relapse samples, validating its clinical relevance. Therapeutically targeting the G1S cell cycle restriction point (with CDK4/6 inhibitor, palbociclib and KAT6A inhibitor, WM-1119, to upregulate CDKN2A) synergized with chemotherapy. Additionally, direct promotion of apoptosis with venetoclax, showed substantial synergy with chemotherapy, overcoming resistance mediated by impaired cell cycle arrest. Altogether, we identify defective cell cycle arrest as a clinically relevant contributor to chemoresistance and identify rationally designed therapeutic combinations that enhance response in AML, potentially circumventing chemoresistance.
Asunto(s)
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Ciclo Celular , Citarabina/farmacología , Citarabina/uso terapéutico , Apoptosis , Puntos de Control del Ciclo Celular , Línea Celular TumoralRESUMEN
Aim: Adult mammalian cardiomyocytes are incapable of significant proliferation, limiting regeneration after myocardial injury. Overexpression of the transcription factor Myc has been shown to drive proliferation in the adult mouse heart, but only when combined with Cyclin T1. As constitutive HRas activity has been shown to stabilise Cyclin T1 in vivo, we aimed to establish whether Myc and HRas could also act cooperatively to induce proliferation in adult mammalian cardiomyocytes in vivo. Methods and results: Using a genetically modified mouse model, we confirmed that constitutive HRas activity (HRas G 12 V ) increased Cyclin T1 expression. HRas G 12 V and constitutive Myc expression together co-operate to drive cell-cycle progression of adult mammalian cardiomyocytes. However, stimulation of endogenous cardiac proliferation by the ectopic expression of HRas G 12 V and Myc also induced cardiomyocyte death, while Myc and Cyclin T1 expression did not. Conclusion: Co-expression of Cyclin T1 and Myc may be a therapeutically tractable approach for cardiomyocyte neo-genesis post injury, while cell death induced by HRas G 12 V and Myc expression likely limits this option as a regenerative therapeutic target.
RESUMEN
Myeloproliferative neoplasms (MPNs) are a group of blood cancers that are maintained by stem cell populations. In this issue of JEM, Dagher et al. (https://doi.org/10.1084/jem.20201268) combine arsenic and interferon α to deliver a knockout punch to MPN stem cells and provide new hope to cure patients with MPNs.
Asunto(s)
Neoplasias Hematológicas , Trastornos Mieloproliferativos , Antivirales , Humanos , Células MadreRESUMEN
Myeloproliferative neoplasms (MPNs) constitute a group of disorders identified by an overproduction of cells derived from myeloid lineage. The majority of MPNs have an identifiable driver mutation responsible for cytokine-independent proliferative signalling. The acquisition of coexisting mutations in chromatin modifiers, spliceosome complex components, DNA methylation modifiers, tumour suppressors and transcriptional regulators have been identified as major pathways for disease progression and leukemic transformation. They also confer different sensitivities to therapeutic options. This review will explore the molecular basis of MPN pathogenesis and specifically examine the impact of coexisting mutations on disease biology and therapeutic options.
Asunto(s)
Trasplante de Médula Ósea/métodos , Progresión de la Enfermedad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Mutación , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/genética , Animales , Humanos , Ratones , Trastornos Mieloproliferativos/clasificación , Trastornos Mieloproliferativos/patología , Fenotipo , Pronóstico , Trasplante HomólogoRESUMEN
The caudal-related homeobox transcription factor CDX2 is expressed in leukemic cells but not during normal blood formation. Retroviral overexpression of Cdx2 induces AML in mice, however the developmental stage at which CDX2 exerts its effect is unknown. We developed a conditionally inducible Cdx2 mouse model to determine the effects of in vivo, inducible Cdx2 expression in hematopoietic stem and progenitor cells (HSPCs). Cdx2-transgenic mice develop myelodysplastic syndrome with progression to acute leukemia associated with acquisition of additional driver mutations. Cdx2-expressing HSPCs demonstrate enrichment of hematopoietic-specific enhancers associated with pro-differentiation transcription factors. Furthermore, treatment of Cdx2 AML with azacitidine decreases leukemic burden. Extended scheduling of low-dose azacitidine shows greater efficacy in comparison to intermittent higher-dose azacitidine, linked to more specific epigenetic modulation. Conditional Cdx2 expression in HSPCs is an inducible model of de novo leukemic transformation and can be used to optimize treatment in high-risk AML.
Asunto(s)
Factor de Transcripción CDX2/metabolismo , Células Madre Hematopoyéticas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Síndromes Mielodisplásicos/metabolismo , Animales , Factor de Transcripción CDX2/genética , Transformación Celular Neoplásica , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/fisiopatologíaRESUMEN
It is unclear why some tissues are refractory to the mitogenic effects of the oncogene Myc. Here we show that Myc activation induces rapid transcriptional responses followed by proliferation in some, but not all, organs. Despite such disparities in proliferative response, Myc is bound to DNA at open elements in responsive (liver) and non-responsive (heart) tissues, but fails to induce a robust transcriptional and proliferative response in the heart. Using heart as an exemplar of a non-responsive tissue, we show that Myc-driven transcription is re-engaged in mature cardiomyocytes by elevating levels of the positive transcription elongation factor (P-TEFb), instating a large proliferative response. Hence, P-TEFb activity is a key limiting determinant of whether the heart is permissive for Myc transcriptional activation. These data provide a greater understanding of how Myc transcriptional activity is determined and indicate modification of P-TEFb levels could be utilised to drive regeneration of adult cardiomyocytes for the treatment of heart myopathies.
Asunto(s)
Miocardio/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Transcripción Genética , Animales , Proliferación Celular/genética , Cromatina/metabolismo , Ciclina T/metabolismo , Ratones , Miocitos Cardíacos/metabolismo , Especificidad de Órganos , Fosforilación , Factor B de Elongación Transcripcional Positiva/metabolismo , Unión Proteica , Proteínas Proto-Oncogénicas c-myc/metabolismo , Activación Transcripcional/genéticaRESUMEN
JAK2V617F is the most common mutation in patients with BCR-ABL negative myeloproliferative neoplasms (MPNs). The eradication of JAK2V617F hematopoietic stem cells (HSCs) is critical for achieving molecular remissions and cure. We investigate the distinct effects of two therapies, ruxolitinib (JAK1/2 inhibitor) and interferon-alpha (IFN-α), on the disease-initiating HSC population. Whereas ruxolitinib inhibits Stat5 activation in erythroid progenitor populations, it fails to inhibit this same pathway in HSCs. In contrast, IFN-α has direct effects on HSCs. Furthermore, STAT1 phosphorylation and pathway activation is greater after IFN-α stimulation in Jak2V617F murine HSCs with increased induction of reactive oxygen species, DNA damage and reduction in quiescence after chronic IFN-α treatment. Interestingly, ruxolitinib does not block IFN-α induced reactive oxygen species and DNA damage in Jak2V617F murine HSCs in vivo. This work provides a mechanistic rationale informing how pegylated IFN-α reduces JAK2V617F allelic burden in the clinical setting and may inform future clinical efforts to combine ruxolitinib with pegylated IFN-α in patients with MPN.
Asunto(s)
Células Madre Hematopoyéticas/efectos de los fármacos , Interferón-alfa/farmacología , Janus Quinasa 2/genética , Mutación , Trastornos Mieloproliferativos/tratamiento farmacológico , Pirazoles/farmacología , Factor de Transcripción STAT1/metabolismo , Animales , Antivirales/farmacología , Proliferación Celular , Células Cultivadas , Quimioterapia Combinada , Femenino , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Nitrilos , Pirimidinas , Factor de Transcripción STAT1/genéticaRESUMEN
The three-dimensional organization of the genome contributes to its maintenance and regulation. While chromosomal regions associate with nucleolar ribosomal RNA genes (rDNA), the biological significance of rDNA-genome interactions and whether they are dynamically regulated during disease remain unclear. rDNA chromatin exists in multiple inactive and active states and their transition is regulated by the RNA polymerase I transcription factor UBTF. Here, using a MYC-driven lymphoma model, we demonstrate that during malignant progression the rDNA chromatin converts to the open state, which is required for tumor cell survival. Moreover, this rDNA transition co-occurs with a reorganization of rDNA-genome contacts which correlate with gene expression changes at associated loci, impacting gene ontologies including B-cell differentiation, cell growth and metabolism. We propose that UBTF-mediated conversion to open rDNA chromatin during malignant transformation contributes to the regulation of specific gene pathways that regulate growth and differentiation through reformed long-range physical interactions with the rDNA.
Asunto(s)
Transformación Celular Neoplásica/genética , ADN Ribosómico/genética , Genes de ARNr , Predisposición Genética a la Enfermedad , Genoma , ARN Polimerasa II/genética , Línea Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina , Progresión de la Enfermedad , Epistasis Genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologíaRESUMEN
Myeloproliferative neoplasms (MPNs) are a group of blood cancers that arise following the sequential acquisition of genetic lesions in hematopoietic stem and progenitor cells (HSPCs). We identify mutational cooperation between Jak2V617F expression and Dnmt3a loss that drives progression from early-stage polycythemia vera to advanced myelofibrosis. Using in vivo, clustered regularly interspaced short palindromic repeats (CRISPR) with CRISPR-associated protein 9 (Cas9) disruption of Dnmt3a in Jak2V617F knockin HSPC, we show that Dnmt3a loss blocks the accumulation of erythroid elements and causes fibrotic infiltration within the bone marrow and spleen. Transcriptional analysis and integration with human data sets identified a core DNMT3A-driven gene-expression program shared across multiple models and contexts of Dnmt3a loss. Aberrant self-renewal and inflammatory signaling were seen in Dnmt3a-/- Jak2V617F HSPC, driven by increased chromatin accessibility at enhancer elements. These findings identify oncogenic cooperativity between Jak2V617F-driven MPN and Dnmt3a loss, leading to activation of HSPC enhancer-driven inflammatory signaling.
Asunto(s)
Sustitución de Aminoácidos , ADN (Citosina-5-)-Metiltransferasas , Neoplasias Hematológicas , Células Madre Hematopoyéticas , Mutación Missense , Mielofibrosis Primaria , Transducción de Señal/genética , Animales , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , Neoplasias Hematológicas/enzimología , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Células Madre Hematopoyéticas/enzimología , Células Madre Hematopoyéticas/patología , Humanos , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Ratones , Ratones Mutantes , Mielofibrosis Primaria/enzimología , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/patologíaRESUMEN
While genetically engineered mice have made an enormous contribution towards the elucidation of human disease, it has hitherto not been possible to tune up or down the level of expression of any endogenous gene. Here we describe compound genetically modified mice in which expression of the endogenous E2f3 gene may be either reversibly elevated or repressed in adult animals by oral administration of tetracycline. This technology is, in principle, applicable to any endogenous gene, allowing direct determination of both elevated and reduced gene expression in physiological and pathological processes. Applying this switchable technology to the key cell cycle transcription factor E2F3, we demonstrate that elevated levels of E2F3 drive ectopic proliferation in multiple tissues. By contrast, E2F3 repression has minimal impact on tissue proliferation or homeostasis in the majority of contexts due to redundancy of adult function with E2F1 and E2F2. In the absence of E2F1 and E2F2, however, repression of E2F3 elicits profound reduction of proliferation in the hematopoietic compartments that is rapidly lethal in adult animals.
Asunto(s)
Factor de Transcripción E2F3/genética , Ingeniería Genética/métodos , Tetraciclina/administración & dosificación , Animales , Proliferación Celular , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Regiones Promotoras Genéticas , Tetraciclina/farmacología , Regulación hacia ArribaRESUMEN
The Eµ-Myc mouse is an extensively used model of MYC driven malignancy; however to date there has only been partial characterization of MYC co-operative mutations leading to spontaneous lymphomagenesis. Here we sequence spontaneously arising Eµ-Myc lymphomas to define transgene architecture, somatic mutations, and structural alterations. We identify frequent disruptive mutations in the PRC1-like component and BCL6-corepressor gene Bcor. Moreover, we find unexpected concomitant multigenic lesions involving Cdkn2a loss and other cancer genes including Nras, Kras and Bcor. These findings challenge the assumed two-hit model of Eµ-Myc lymphoma and demonstrate a functional in vivo role for Bcor in suppressing tumorigenesis.
Asunto(s)
Linfocitos B/metabolismo , Regulación Neoplásica de la Expresión Génica , Linfoma de Células B/genética , Mutación , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Represoras/genética , Alelos , Animales , Linfocitos B/inmunología , Linfocitos B/patología , Sistemas CRISPR-Cas , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/inmunología , Modelos Animales de Enfermedad , Edición Génica , Frecuencia de los Genes , Janus Quinasa 2/genética , Janus Quinasa 2/inmunología , Linfoma de Células B/inmunología , Linfoma de Células B/patología , Ratones , Ratones Transgénicos , Proteínas Proto-Oncogénicas c-myc/inmunología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/inmunología , Proteínas Represoras/inmunología , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/inmunología , Transcriptoma , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/inmunología , Secuenciación Completa del GenomaRESUMEN
UNLABELLED: Ribosome biogenesis and protein synthesis are dysregulated in many cancers, with those driven by the proto-oncogene c-MYC characterized by elevated Pol I-mediated ribosomal rDNA transcription and mTORC1/eIF4E-driven mRNA translation. Here, we demonstrate that coordinated targeting of rDNA transcription and PI3K-AKT-mTORC1-dependent ribosome biogenesis and protein synthesis provides a remarkable improvement in survival in MYC-driven B lymphoma. Combining an inhibitor of rDNA transcription (CX-5461) with the mTORC1 inhibitor everolimus more than doubled survival of Eµ-Myc lymphoma-bearing mice. The ability of each agent to trigger tumor cell death via independent pathways was central to their synergistic efficacy. CX-5461 induced nucleolar stress and p53 pathway activation, whereas everolimus induced expression of the proapoptotic protein BMF that was independent of p53 and reduced expression of RPL11 and RPL5. Thus, targeting the network controlling the synthesis and function of ribosomes at multiple points provides a potential new strategy to treat MYC-driven malignancies. SIGNIFICANCE: Treatment options for the high proportion of cancers driven by MYC are limited. We demonstrate that combining pharmacologic targeting of ribosome biogenesis and mTORC1-dependent translation provides a remarkable therapeutic benefit to Eµ-Myc lymphoma-bearing mice. These results establish a rationale for targeting ribosome biogenesis and function to treat MYC-driven cancer.
Asunto(s)
Benzotiazoles/administración & dosificación , ADN Ribosómico/antagonistas & inhibidores , Everolimus/administración & dosificación , Linfoma de Células B/terapia , Naftiridinas/administración & dosificación , Proteínas Proto-Oncogénicas c-myc/genética , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Benzotiazoles/farmacología , Sinergismo Farmacológico , Everolimus/farmacología , Humanos , Linfoma de Células B/genética , Ratones , Naftiridinas/farmacología , Biosíntesis de Proteínas/efectos de los fármacos , Proto-Oncogenes Mas , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia , Transcripción Genética/efectos de los fármacos , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are among the most common mutations found in human cancer and have also recently been implicated in a range of overgrowth syndromes in humans. We have used a novel inducible "exon-switch" approach to knock in the constitutively active Pik3ca(H1047R) mutation into the endogenous Pik3ca gene of the mouse. Ubiquitous expression of the Pik3ca(H1047R) mutation throughout the body resulted in a dramatic increase in body weight within 3 weeks of induction (mutant 150 ± 5%; wild-type 117 ± 3%, mean ± sem), which was associated with increased organ size rather than adiposity. Severe metabolic effects, including a reduction in blood glucose levels to 59 ± 4% of baseline (11 days postinduction) and undetectable insulin levels, were also observed. Pik3ca(H1047R) mutant mice died earlier (median survival 46.5 d post-mutation induction) than wild-type control mice (100% survival > 250 days). Although deletion of Akt2 increased median survival by 44%, neither organ overgrowth, nor hypoglycemia were rescued, indicating that both the growth and metabolic functions of constitutive PI3K activity can be Akt2 independent. This mouse model demonstrates the critical role of PI3K in the regulation of both organ size and glucose metabolism at the whole animal level.
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Hipoglucemia/enzimología , Hipoglucemia/genética , Insulina/sangre , Mutación , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Sustitución de Aminoácidos , Animales , Fosfatidilinositol 3-Quinasa Clase I , Femenino , Expresión Génica , Técnicas de Sustitución del Gen , Glucosa/metabolismo , Humanos , Hipoglucemia/metabolismo , Ratones , Ratones Noqueados , Ratones Mutantes , Ratones Transgénicos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Tamaño de los Órganos/genética , Tamaño de los Órganos/fisiología , Proteínas Proto-Oncogénicas c-akt/deficiencia , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Aumento de PesoRESUMEN
Mutations that directly affect transcription by RNA polymerases rank among the most central mediators of malignant transformation, but the frequency of new anticancer drugs that selectively target defective transcription apparatus entering the clinic has been limited. This is because targeting the large protein-protein and protein-DNA interfaces that control both generic and selective aspects of RNA polymerase transcription has proved extremely difficult. However, recent technological advances have led to a 'quantum leap' in our comprehension of the structure and function of the core RNA polymerase components, how they are dysregulated in a broad range of cancers and how they may be targeted for 'transcription therapy'.
Asunto(s)
ARN Polimerasas Dirigidas por ADN/fisiología , Neoplasias/enzimología , Animales , Antineoplásicos/farmacología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Terapia Molecular Dirigida , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Oncogenes , Factores Generales de Transcripción/genética , Factores Generales de Transcripción/metabolismo , Activación Transcripcional/efectos de los fármacosRESUMEN
The dysregulation of PI3K/AKT/mTORC1 signalling and/or hyperactivation of MYC are observed in a high proportion of human cancers, and together they form a 'super signalling' network mediating malignancy. A fundamental downstream action of this signalling network is up-regulation of ribosome biogenesis and subsequent alterations in the patterns of translation and increased protein synthesis, which are thought to be critical for AKT/MYC-driven oncogenesis. We have demonstrated that AKT and MYC cooperate to drive ribosomal DNA (rDNA) transcription and ribosome biogenesis, with AKT being essential for rDNA transcription and in vitro survival of lymphoma cells isolated from a MYC-driven model of B-cell lymphoma (Eµ-Myc) [Chan JC et al., (2011) Science Signalling 4, ra56]. Here we show that the allosteric AKT inhibitor MK-2206 rapidly and potently antagonizes rDNA transcription in Eµ-Myc B-cell lymphomas in vivo, and this is associated with a rapid reduction in indicators of disease burden, including spleen weight and the abundance of tumour cells in both the circulation and lymph nodes. Extended treatment of tumour-bearing mice with MK-2206 resulted in a significant delay in disease progression, associated with increased B-cell lymphoma apoptosis. Our findings suggest that malignant diseases characterized by unrestrained ribosome biogenesis may be vulnerable to therapeutic strategies that target the PI3K/AKT/mTORC1/MYC growth control network.