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1.
Cell ; 171(2): 481-494.e15, 2017 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-28985567

RESUMEN

Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.


Asunto(s)
Sistemas CRISPR-Cas , Perfilación de la Expresión Génica , Linfoma de Células B Grandes Difuso/genética , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Células Cultivadas , Exoma , Femenino , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Rituximab/administración & dosificación
2.
Nature ; 569(7757): 503-508, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31068700

RESUMEN

Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from individuals of various lineages and ethnicities. Integration of these data with functional characterizations such as drug-sensitivity, short hairpin RNA knockdown and CRISPR-Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers. Together, this dataset and an accompanying public data portal provide a resource for the acceleration of cancer research using model cancer cell lines.


Asunto(s)
Línea Celular Tumoral , Neoplasias/genética , Neoplasias/patología , Antineoplásicos/farmacología , Biomarcadores de Tumor , Metilación de ADN , Resistencia a Antineoplásicos , Etnicidad/genética , Edición Génica , Histonas/metabolismo , Humanos , MicroARNs/genética , Terapia Molecular Dirigida , Neoplasias/metabolismo , Análisis por Matrices de Proteínas , Empalme del ARN
3.
Cell ; 137(6): 1062-75, 2009 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-19524509

RESUMEN

Allelic loss of the essential autophagy gene beclin1 occurs in human cancers and renders mice tumor-prone suggesting that autophagy is a tumor-suppression mechanism. While tumor cells utilize autophagy to survive metabolic stress, autophagy also mitigates the resulting cellular damage that may limit tumorigenesis. In response to stress, autophagy-defective tumor cells preferentially accumulated p62/SQSTM1 (p62), endoplasmic reticulum (ER) chaperones, damaged mitochondria, reactive oxygen species (ROS), and genome damage. Moreover, suppressing ROS or p62 accumulation prevented damage resulting from autophagy defects indicating that failure to regulate p62 caused oxidative stress. Importantly, sustained p62 expression resulting from autophagy defects was sufficient to alter NF-kappaB regulation and gene expression and to promote tumorigenesis. Thus, defective autophagy is a mechanism for p62 upregulation commonly observed in human tumors that contributes directly to tumorigenesis likely by perturbing the signal transduction adaptor function of p62-controlling pathways critical for oncogenesis.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Autofagia , Neoplasias/metabolismo , Aneuploidia , Animales , Apoptosis , Línea Celular , Retículo Endoplásmico/metabolismo , Humanos , Ratones , Mitocondrias/metabolismo , Chaperonas Moleculares/metabolismo , FN-kappa B/metabolismo , Neoplasias/genética , Estrés Oxidativo , Proteína Disulfuro Isomerasas/metabolismo , Proteína Sequestosoma-1 , Factor de Transcripción TFIIH , Factores de Transcripción
4.
Oncologist ; 28(2): e115-e123, 2023 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-36427020

RESUMEN

BACKGROUND: Ulixertinib is a novel oral ERK inhibitor that has shown promising single-agent activity in a phase I clinical trial that included patients with RAS-mutant cancers. METHODS: We conducted a phase Ib trial combining ulixertinib with gemcitabine and nab-paclitaxel (GnP) for untreated metastatic pancreatic adenocarcinoma. The trial comprised a dose de-escalation part and a cohort expansion part at the recommended phase II dose (RP2D). Primary endpoint was to determine the RP2D of ulixertinib plus GnP and secondary endpoints were to assess toxicity and safety profile, biochemical and radiographic response, progression-free survival (PFS) and overall survival (OS). RESULTS: Eighteen patients were enrolled. Ulixertinib 600 mg PO twice daily (BID) with GnP was initially administered but was de-escalated to 450 mg BID as RP2D early during dose expansion due to poor tolerability, which ultimately led to premature termination of the study. Common treatment-related adverse events (TRAEs) were anemia, thrombocytopenia, rash and diarrhea. For 5 response evaluable patients, one patient achieved a partial response and 2 patients achieved stable disease. For 15 patients who received the triplet, median PFS and OS were 5.46 and 12.23 months, respectively. CONCLUSION: Ulixertinib plus GnP had similar frequency of grade ≥3 TRAEs and potentially efficacy as GnP, however was complicated by a high rate of all-grade TRAEs (ClinicalTrials.gov Identifier: NCT02608229).


Asunto(s)
Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Gemcitabina , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Desoxicitidina , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Paclitaxel , Albúminas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del Tratamiento
5.
Blood ; 138(26): 2874-2885, 2021 12 30.
Artículo en Inglés | MEDLINE | ID: mdl-34115118

RESUMEN

Donor and recipient cytomegalovirus (CMV) serostatus correlate with transplant-related mortality that is associated with reduced survival following allogeneic stem cell transplant (SCT). Prior epidemiologic studies have suggested that CMV seronegative recipients (R-) receiving a CMV-seropositive graft (D+) experience inferior outcomes compared with other serostatus combinations, an observation that appears independent of viral reactivation. We therefore investigated the hypothesis that prior donor CMV exposure irreversibly modifies immunologic function after SCT. We identified a CD4+/CD57+/CD27- T-cell subset that was differentially expressed between D+ and D- transplants and validated results with 120 patient samples. This T-cell subset represents an average of 2.9% (D-/R-), 18% (D-/R+), 12% (D+/R-), and 19.6% (D+/R+) (P < .0001) of the total CD4+ T-cell compartment and stably persists for at least several years post-SCT. Even in the absence of CMV reactivation post-SCT, D+/R- transplants displayed a significant enrichment of these cells compared with D-/R- transplants (P = .0078). These are effector memory cells (CCR7-/CD45RA+/-) that express T-bet, Eomesodermin, granzyme B, secrete Th1 cytokines, and are enriched in CMV-specific T cells. These cells are associated with decreased T-cell receptor diversity (P < .0001) and reduced proportions of major histocompatibility class (MHC) II expressing classical monocytes (P < .0001), myeloid (P = .024), and plasmacytoid dendritic cells (P = .0014). These data describe a highly expanded CD4+ T-cell population and putative mechanisms by which prior donor or recipient CMV exposure may create a lasting immunologic imprint following SCT, providing a rationale for using D- grafts for R- transplant recipients.


Asunto(s)
Antígenos CD4/inmunología , Antígenos CD57/inmunología , Infecciones por Citomegalovirus/inmunología , Citomegalovirus/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Células T de Memoria/inmunología , Antígenos CD4/análisis , Linfocitos T CD4-Positivos/inmunología , Antígenos CD57/análisis , Células Cultivadas , Citomegalovirus/aislamiento & purificación , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/inmunología , Humanos , Donantes de Tejidos , Trasplante Homólogo/efectos adversos
6.
Blood ; 134(19): 1598-1607, 2019 11 07.
Artículo en Inglés | MEDLINE | ID: mdl-31558468

RESUMEN

Burkitt lymphoma (BL) is an aggressive, MYC-driven lymphoma comprising 3 distinct clinical subtypes: sporadic BLs that occur worldwide, endemic BLs that occur predominantly in sub-Saharan Africa, and immunodeficiency-associated BLs that occur primarily in the setting of HIV. In this study, we comprehensively delineated the genomic basis of BL through whole-genome sequencing (WGS) of 101 tumors representing all 3 subtypes of BL to identify 72 driver genes. These data were additionally informed by CRISPR screens in BL cell lines to functionally annotate the role of oncogenic drivers. Nearly every driver gene was found to have both coding and non-coding mutations, highlighting the importance of WGS for identifying driver events. Our data implicate coding and non-coding mutations in IGLL5, BACH2, SIN3A, and DNMT1. Epstein-Barr virus (EBV) infection was associated with higher mutation load, with type 1 EBV showing a higher mutational burden than type 2 EBV. Although sporadic and immunodeficiency-associated BLs had similar genetic profiles, endemic BLs manifested more frequent mutations in BCL7A and BCL6 and fewer genetic alterations in DNMT1, SNTB2, and CTCF. Silencing mutations in ID3 were a common feature of all 3 subtypes of BL. In vitro, mass spectrometry-based proteomics demonstrated that the ID3 protein binds primarily to TCF3 and TCF4. In vivo knockout of ID3 potentiated the effects of MYC, leading to rapid tumorigenesis and tumor phenotypes consistent with those observed in the human disease.


Asunto(s)
Linfoma de Burkitt/genética , Secuenciación Completa del Genoma/métodos , Animales , Humanos , Ratones
7.
PLoS Pathog ; 14(5): e1007057, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29775485

RESUMEN

Within the liver a single Plasmodium parasite transforms into thousands of blood-infective forms to cause malaria. Here, we use RNA-sequencing to identify host genes that are upregulated upon Plasmodium berghei infection of hepatocytes with the hypothesis that host pathways are hijacked to benefit parasite development. We found that expression of aquaporin-3 (AQP3), a water and glycerol channel, is significantly induced in Plasmodium-infected hepatocytes compared to uninfected cells. This aquaglyceroporin localizes to the parasitophorous vacuole membrane, the compartmental interface between the host and pathogen, with a temporal pattern that correlates with the parasite's expansion in the liver. Depletion or elimination of host AQP3 expression significantly reduces P. berghei parasite burden during the liver stage and chemical disruption by a known AQP3 inhibitor, auphen, reduces P. falciparum asexual blood stage and P. berghei liver stage parasite load. Further use of this inhibitor as a chemical probe suggests that AQP3-mediated nutrient transport is an important function for parasite development. This study reveals a previously unknown potential route for host-dependent nutrient acquisition by Plasmodium which was discovered by mapping the transcriptional changes that occur in hepatocytes throughout P. berghei infection. The dataset reported may be leveraged to identify additional host factors that are essential for Plasmodium liver stage infection and highlights Plasmodium's dependence on host factors within hepatocytes.


Asunto(s)
Acuaporina 3/metabolismo , Plasmodium berghei/metabolismo , Animales , Acuaporina 3/fisiología , Células Hep G2 , Hepatocitos/metabolismo , Hepatocitos/parasitología , Humanos , Hígado/metabolismo , Hígado/parasitología , Hepatopatías , Malaria/parasitología , Ratones , Parásitos/metabolismo , Plasmodium berghei/genética , Plasmodium berghei/parasitología , Proteínas Protozoarias/metabolismo , Análisis de Secuencia de ARN/métodos , Esporozoítos/metabolismo , Vacuolas/metabolismo
9.
J Clin Immunol ; 39(7): 678-687, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31377970

RESUMEN

PURPOSE: To evaluate mortality risk factors in pediatric-onset common variable immunodeficiency disorders (CVID), we evaluated the largest single-institution cohort of pediatric-onset CVID patients. Previous publications on CVID have provided valuable descriptive data, but lack risk stratification to guide physicians in management of these patients. METHODS: Retrospective chart review of 198 subjects with CVID at a single institution, of whom 91 had disease onset at a pediatric age. Clinical and laboratory data were collected at diagnosis and in follow-up. Odds ratios and Fisher tests were utilized to examine trends. This study was approved by an institutional review board. RESULTS: Clinical features and laboratory results for subjects diagnosed with CVID at a pediatric age are similar to those who had adult-onset CVID. However, majority of the deceased subjects (13/18) were at a pediatric age at CVID symptom onset. These subjects had a lower age at mortality, multiple comorbidities, and often depression. The most common cause of death was infection. Lung disease (OR 5, p < 0.05) and infection with severe/opportunistic organisms (OR 9, p < 0.05) are directly related to increased mortality. Delay in diagnosis of CVID is also correlated with mortality. Intermediary markers correlating with mortality include anemia, GERD, and depression. CONCLUSIONS: There are many similarities between patients with pediatric- and adult-onset CVID; however, the mortality of pediatric CVID in our cohort is striking. This is the first study to identify specific factors correlated with mortality in pediatric-onset CVID to guide pediatricians and subspecialists in managing these immunodeficient patients.


Asunto(s)
Inmunodeficiencia Variable Común/epidemiología , Adolescente , Adulto , Edad de Inicio , Niño , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/etiología , Inmunodeficiencia Variable Común/mortalidad , Comorbilidad , Diagnóstico Tardío , Susceptibilidad a Enfermedades , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Mortalidad , Oportunidad Relativa , Fenotipo , Pronóstico , Adulto Joven
10.
Blood ; 130(16): 1819-1831, 2017 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-28801451

RESUMEN

The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressive lymphomas with poor clinical outcome. High-resolution structural and functional genomic analysis of adult Burkitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene signature (adult-molecularly defined BL [mBL]) revealed the MYC-ARF-p53 axis as the primary deregulated pathway. Adult-mBL had either unique or more frequent genomic aberrations (del13q14, del17p, gain8q24, and gain18q21) compared with pediatric-mBL, but shared commonly mutated genes. Mutations in genes promoting the tonic B-cell receptor (BCR)→PI3K pathway (TCF3 and ID3) did not differ by age, whereas effectors of chronic BCR→NF-κB signaling were associated with adult-mBL. A subset of adult-mBL had BCL2 translocation and mutation and elevated BCL2 mRNA and protein expression, but had a mutation profile similar to mBL. These double-hit lymphomas may have arisen from a tumor precursor that acquired both BCL2 and MYC translocations and/or KMT2D (MLL2) mutation. Gain/amplification of MIR17HG and its paralogue loci was observed in 50% of adult-mBL. In vitro studies suggested miR-17∼92's role in constitutive activation of BCR signaling and sensitivity to ibrutinib. Overall integrative analysis identified an interrelated gene network affected by copy number and mutation, leading to disruption of the p53 pathway and the BCR→PI3K or NF-κB activation, which can be further exploited in vivo by small-molecule inhibitors for effective therapy in adult-mBL.


Asunto(s)
Linfoma de Burkitt/genética , Regulación Neoplásica de la Expresión Génica , Linfoma de Células B/genética , Transcriptoma , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos B/patología , Línea Celular Tumoral , Niño , Preescolar , Femenino , Humanos , Inmunofenotipificación , Linfoma de Células B/patología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Clasificación del Tumor , Adulto Joven
11.
Hematol Oncol ; 37(4): 375-382, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31408531

RESUMEN

In large B-cell lymphoma (LBCL), MYC translocation and MYC/BCL2 or MYC/BCL6 double hit (DH) are associated with poor prognosis, and there is an unmet need for novel treatment targets in this patient group. Treatments targeting the PD-L1/PD-1 pathway are still poorly elucidated in LBCL. PD-L1 expression might predict response to treatment targeting the PD-L1/PD-1 pathway. We therefore investigated the relationship between PD-L1 protein and mRNA expression levels and MYC and DH translocation in LBCL. We detected MYC, BCL2, and BCL6 translocation by fluorescent in situ hybridization in tissue samples from 130 patients randomly selected from two cohorts of patients with LBCL: 49 patients with MYC translocation of whom 36 had DH and 81 without MYC translocation. PD-L1 protein expression was detected by immunohistochemistry (IHC) in tissue samples from 77 patients and PD-L1 mRNA expression by next-generation RNA sequencing (NGS) in another 77 patients. Twenty-four patients overlapped, ie, were analysed with both IHC and NGS. Nonparametric tests were performed to evaluate intergroup differences. PD-L1 protein expression level was significantly lower in patients with MYC (n = 42, median = 3.3%, interquartile range [IQR] 0.0-10.8) or DH translocations (n = 31, median = 3.3%, IQR 0.0-10.0) compared with patients with no MYC (n = 35, median = 16.7%, IQR 3.3-30.0) or no DH translocations (n = 46, 13.3%, IQR 2.5-30.0), P = .004 and P ≤ .001, respectively. PD-L1 mRNA expression was also significantly lower in patients with MYC or DH translocations, P = .001 and P = .006, respectively. Higher PD-L1 protein and mRNA expression levels were associated with non-germinal centre (GC) type compared with germinal centre B-cell (GCB)-type diffuse LBCL (DLBCL), P = .004 and P = .002, respectively. In conclusion, we report an association between low PD-L1 expression and MYC and DH translocation in patients with LBCL. Our findings may indicate that patients with MYC or DH translocation may benefit less from treatment with PD-L1/PD-1-inhibitors compared with patients without these translocations. This should be evaluated in larger, prospective, consecutive trials.


Asunto(s)
Antígeno B7-H1/biosíntesis , Regulación Neoplásica de la Expresión Génica , Genes myc , Linfoma de Células B Grandes Difuso/metabolismo , Proteínas de Neoplasias/biosíntesis , ARN Mensajero/biosíntesis , ARN Neoplásico/biosíntesis , Translocación Genética , Adulto , Anciano , Subgrupos de Linfocitos B/metabolismo , Subgrupos de Linfocitos B/patología , Antígeno B7-H1/genética , Femenino , Perfilación de la Expresión Génica , Genes bcl-2 , Centro Germinal/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Proteínas Proto-Oncogénicas c-bcl-6/genética , ARN Mensajero/genética , ARN Neoplásico/genética , Estudios Retrospectivos
12.
J Immunol ; 198(8): 3136-3148, 2017 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-28258199

RESUMEN

Inhibitor of DNA binding (Id) proteins, including Id1-4, are transcriptional regulators involved in promoting cell proliferation and survival in various cell types. Although upregulation of Id proteins is associated with a broad spectrum of tumors, recent studies have identified that Id3 plays a tumor-suppressor role in the development of Burkitt's lymphoma in humans and hepatosplenic T cell lymphomas in mice. In this article, we report rapid lymphoma development in Id2/Id3 double-knockout mice that is caused by unchecked expansion of invariant NKT (iNKT) cells or a unique subset of innate-like CD1d-independent T cells. These populations began to expand in neonatal mice and, upon malignant transformation, resulted in mortality between 3 and 11 mo of age. The malignant cells also gave rise to lymphomas upon transfer to Rag-deficient and wild-type hosts, reaffirming their inherent tumorigenic potential. Microarray analysis revealed a significantly modified program in these neonatal iNKT cells that ultimately led to their malignant transformation. The lymphoma cells demonstrated chromosome instability along with upregulation of several signaling pathways, including the cytokine-cytokine receptor interaction pathway, which can promote their expansion and migration. Dysregulation of genes with reported driver mutations and the NF-κB pathway were found to be shared between Id2/Id3 double-knockout lymphomas and human NKT tumors. Our work identifies a distinct premalignant state and multiple tumorigenic pathways caused by loss of function of Id2 and Id3. Thus, conditional deletion of Id2 and Id3 in developing T cells establishes a unique animal model for iNKT and relevant innate-like lymphomas.


Asunto(s)
Proteína 2 Inhibidora de la Diferenciación/inmunología , Proteínas Inhibidoras de la Diferenciación/inmunología , Linfoma/inmunología , Células T Asesinas Naturales/inmunología , Subgrupos de Linfocitos T/inmunología , Traslado Adoptivo , Animales , Separación Celular , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/metabolismo , Modelos Animales de Enfermedad , Citometría de Flujo , Humanos , Linfoma/patología , Ratones , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa
13.
Nature ; 483(7391): 603-7, 2012 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-22460905

RESUMEN

The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.


Asunto(s)
Bases de Datos Factuales , Ensayos de Selección de Medicamentos Antitumorales/métodos , Enciclopedias como Asunto , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antineoplásicos/farmacología , Línea Celular Tumoral , Linaje de la Célula , Cromosomas Humanos/genética , Ensayos Clínicos como Asunto/métodos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Genes ras/genética , Genoma Humano/genética , Genómica , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Farmacogenética , Células Plasmáticas/citología , Células Plasmáticas/efectos de los fármacos , Células Plasmáticas/metabolismo , Medicina de Precisión/métodos , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/metabolismo , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Análisis de Secuencia de ADN , Inhibidores de Topoisomerasa/farmacología
14.
Cancer Res Commun ; 3(6): 969-979, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37377612

RESUMEN

Ribosomes in cancer cells accumulate numerous patient-specific structural and functional modifications that facilitate tumor progression by modifying protein translation. We have taken a unique synthetic chemistry approach to generate novel macrolides, Ribosome modulating agents (RMA), that are proposed to act distal to catalytic sites and exploit cancer ribosome heterogeneity. The RMA ZKN-157 shows two levels of selectivity: (i) selective translation inhibition of a subset of proteins enriched for components of the ribosome and protein translation machinery that are upregulated by MYC; and (ii) selective inhibition of proliferation of a subset of colorectal cancer cell lines. Mechanistically, the selective ribosome targeting in sensitive cells triggered cell-cycle arrest and apoptosis. Consequently, in colorectal cancer, sensitivity to ZKN-157 in cell lines and patient-derived organoids was restricted to the consensus molecular subtype 2 (CMS2) subtype that is distinguished by high MYC and WNT pathway activity. ZKN-157 showed efficacy as single agent and, the potency and efficacy of ZKN-157 synergized with clinically approved DNA-intercalating agents which have previously been shown to inhibit ribogenesis as well. ZKN-157 thus represents a new class of ribosome modulators that display cancer selectivity through specific ribosome inhibition in the CMS2 subtype of colorectal cancer potentially targeting MYC-driven addiction to high protein translation. Significance: This study demonstrates that ribosome heterogeneity in cancer can be exploited to develop selective ribogenesis inhibitors. The colorectal cancer CMS2 subtype, with a high unmet need for therapeutics, shows vulnerability to our novel selective ribosome modulator. The mechanism suggests that other cancer subtypes with high MYC activation could also be targeted.


Asunto(s)
Neoplasias Colorrectales , Biosíntesis de Proteínas , Ribosomas , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Ribosomas/genética , Ribosomas/metabolismo , Puntos de Control del Ciclo Celular
15.
Kidney Cancer J ; 6(3): 179-193, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36684483

RESUMEN

BACKGROUND: SET domain-containing protein 2 (SETD2) is commonly mutated in renal cell carcinoma. SETD2 methylates histone H3 as well as a growing list of non-histone proteins. OBJECTIVE: Initially, we sought to explore SETD2-dependent changes in lysine methylation of proteins in proximal renal tubule cells. Subsequently, we focused on changes in lysine methylation of the translation elongation factor eEF1A1. METHODS: To accomplish these objectives, we initially performed a systems-wide analysis of protein lysine-methylation and expression in wild type (WT) and SETD2-knock out (KO) kidney cells and later focused our studies on eEF1A1 as well as the expression of lysine methyltransferases that regulate its lysine methylation. RESULTS: We observed decreased lysine methylation of the translation elongation factor eEF1A1. EEF1AKMT2 and EEF1AKMT3 are known to methylate eEF1A1, and we show here that their expression is dependent on SET-domain function of SETD2. Globally, we observe differential expression of hundreds of proteins in WT versus SETD2-KO cells, including increased expression of many involved in protein translation. Finally, we observe decreased progression free survival and loss of EEF1AKMT2 gene expression in SETD2-mutated tumors predicted to have loss of function of the SET domain. CONCLUSION: Overall, these data suggest that SETD2-mutated ccRCC, via loss of enzymatic function of the SET domain, displays dysregulation of protein translation as a potentially important component of the transformed phenotype.

16.
JCI Insight ; 7(15)2022 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-35763345

RESUMEN

Integrins - the principal extracellular matrix (ECM) receptors of the cell - promote cell adhesion, migration, and proliferation, which are key events for cancer growth and metastasis. To date, most integrin-targeted cancer therapeutics have disrupted integrin-ECM interactions, which are viewed as critical for integrin functions. However, such agents have failed to improve cancer patient outcomes. We show that the highly expressed integrin ß1 subunit is required for lung adenocarcinoma development in a carcinogen-induced mouse model. Likewise, human lung adenocarcinoma cell lines with integrin ß1 deletion failed to form colonies in soft agar and tumors in mice. Mechanistically, we demonstrate that these effects do not require integrin ß1-mediated adhesion to ECM but are dependent on integrin ß1 cytoplasmic tail-mediated activation of focal adhesion kinase (FAK). These studies support a critical role for integrin ß1 in lung tumorigenesis that is mediated through constitutive, ECM binding-independent signaling involving the cytoplasmic tail.


Asunto(s)
Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , Adenocarcinoma/genética , Adenocarcinoma del Pulmón/genética , Animales , Humanos , Integrina beta1/genética , Integrina beta1/metabolismo , Integrinas , Ligandos , Neoplasias Pulmonares/patología , Ratones
17.
Circulation ; 122(1): 70-9, 2010 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-20566956

RESUMEN

BACKGROUND: Recognition of biological patterns holds promise for improved identification of patients at risk for myocardial infarction (MI) and death. We hypothesized that identifying high- and low-risk patterns from a broad spectrum of hematologic phenotypic data related to leukocyte peroxidase-, erythrocyte- and platelet-related parameters may better predict future cardiovascular risk in stable cardiac patients than traditional risk factors alone. METHODS AND RESULTS: Stable patients (n=7369) undergoing elective cardiac evaluation at a tertiary care center were enrolled. A model (PEROX) that predicts incident 1-year death and MI was derived from standard clinical data combined with information captured by a high-throughput peroxidase-based hematology analyzer during performance of a complete blood count with differential. The PEROX model was developed using a random sampling of subjects in a derivation cohort (n=5895) and then independently validated in a nonoverlapping validation cohort (n=1474). Twenty-three high-risk (observed in > or =10% of subjects with events) and 24 low-risk (observed in > or =10% of subjects without events) patterns were identified in the derivation cohort. Erythrocyte- and leukocyte (peroxidase)-derived parameters dominated the variables predicting risk of death, whereas variables in MI risk patterns included traditional cardiac risk factors and elements from all blood cell lineages. Within the validation cohort, the PEROX model demonstrated superior prognostic accuracy (78%) for 1-year risk of death or MI compared with traditional risk factors alone (67%). Furthermore, the PEROX model reclassified 23.5% (P<0.001) of patients to different risk categories for death/MI when added to traditional risk factors. CONCLUSIONS: Comprehensive pattern recognition of high- and low-risk clusters of clinical, biochemical, and hematologic parameters provided incremental prognostic value in stable patients having elective diagnostic cardiac catheterization for 1-year risks of death and MI.


Asunto(s)
Infarto del Miocardio/epidemiología , Peroxidasas/sangre , Anciano , Angioplastia Coronaria con Balón , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/enzimología , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Hematología/métodos , Humanos , Masculino , Anamnesis , Persona de Mediana Edad , Infarto del Miocardio/sangre , Infarto del Miocardio/enzimología , Infarto del Miocardio/mortalidad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Reproducibilidad de los Resultados , Factores de Riesgo , Tasa de Supervivencia , Factores de Tiempo , Troponina T/sangre
18.
Artículo en Inglés | MEDLINE | ID: mdl-32152246

RESUMEN

Non-Hodgkin lymphomas (NHLs) are a diverse group of entities, both clinically and molecularly. Here, we review the evolution of classification schemes in B-cell lymphoma, noting the now standard WHO classification system that is based on immune cell-of-origin and molecular phenotypes. We review how lymphomas arise throughout the B-cell development process as well as the molecular and clinical features of prominent B-cell lymphomas. We provide an overview of the major progress that has occurred over the past decade in terms of our molecular understanding of these diseases. We discuss treatment options available and focus on a number of the diverse research tools that have been employed to improve our understanding of these diseases. We discuss the problem of heterogeneity in lymphomas and anticipate that the near future will bring significant advances that provide a measurable impact on NHL outcomes.


Asunto(s)
Linfocitos B/patología , Linfoma de Células B/terapia , Linfoma no Hodgkin/terapia , Humanos , Linfoma de Células B/clasificación , Linfoma no Hodgkin/clasificación , Organización Mundial de la Salud
19.
Cancers (Basel) ; 13(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806963

RESUMEN

Predicting response to ICI therapy among patients with renal cell carcinoma (RCC) has been uniquely challenging. We analyzed patient characteristics and clinical correlates from a retrospective single-site cohort of advanced RCC patients receiving anti-PD-1/PD-L1 monotherapy (N = 97), as well as molecular parameters in a subset of patients, including multiplexed immunofluorescence (mIF), whole exome sequencing (WES), T cell receptor (TCR) sequencing, and RNA sequencing (RNA-seq). Clinical factors such as the development of immune-related adverse events (odds ratio (OR) = 2.50, 95% confidence interval (CI) = 1.05-5.91) and immunological prognostic parameters, including a higher percentage of circulating lymphocytes (23.4% vs. 17.4%, p = 0.0015) and a lower percentage of circulating neutrophils (61.8% vs. 68.5%, p = 0.0045), correlated with response. Previously identified gene expression signatures representing pathways of angiogenesis, myeloid inflammation, T effector presence, and clear cell signatures also correlated with response. High PD-L1 expression (>10% cells) as well as low TCR diversity (≤644 clonotypes) were associated with improved progression-free survival (PFS). We corroborate previously published findings and provide preliminary evidence of T cell clonality impacting the outcome of RCC patients. To further biomarker development in RCC, future studies will benefit from integrated analysis of multiple molecular platforms and prospective validation.

20.
Genome Inform ; 24: 139-53, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-22081596

RESUMEN

We develop a general method to identify gene networks from pair-wise correlations between genes in a microarray data set and apply it to a public prostate cancer gene expression data from 69 primary prostate tumors. We define the degree of a node as the number of genes significantly associated with the node and identify hub genes as those with the highest degree. The correlation network was pruned using transcription factor binding information in VisANT (http://visant.bu.edu/) as a biological filter. The reliability of hub genes was determined using a strict permutation test. Separate networks for normal prostate samples, and prostate cancer samples from African Americans (AA) and European Americans (EA) were generated and compared. We found that the same hubs control disease progression in AA and EA networks. Combining AA and EA samples, we generated networks for low low (<7) and high (≥7) Gleason grade tumors. A comparison of their major hubs with those of the network for normal samples identified two types of changes associated with disease: (i) Some hub genes increased their degree in the tumor network compared to their degree in the normal network, suggesting that these genes are associated with gain of regulatory control in cancer (e.g. possible turning on of oncogenes). (ii) Some hubs reduced their degree in the tumor network compared to their degree in the normal network, suggesting that these genes are associated with loss of regulatory control in cancer (e.g. possible loss of tumor suppressor genes). A striking result was that for both AA and EA tumor samples, STAT5a, CEBPB and EGR1 are major hubs that gain neighbors compared to the normal prostate network. Conversely, HIF-lα is a major hub that loses connections in the prostate cancer network compared to the normal prostate network. We also find that the degree of these hubs changes progressively from normal to low grade to high grade disease, suggesting that these hubs are master regulators of prostate cancer and marks disease progression. STAT5a was identified as a central hub, with ~120 neighbors in the prostate cancer network and only 81 neighbors in the normal prostate network. Of the 120 neighbors of STAT5a, 57 are known cancer related genes, known to be involved in functional pathways associated with tumorigenesis. Our method is general and can easily be extended to identify and study networks associated with any two phenotypes.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Neoplasias de la Próstata/metabolismo , Factor de Transcripción STAT5/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Negro o Afroamericano , Algoritmos , Biología Computacional/métodos , Perfilación de la Expresión Génica , Genes Supresores de Tumor , Humanos , Masculino , Neoplasias de la Próstata/etnología , Estados Unidos , Población Blanca
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