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1.
Ann Hematol ; 98(10): 2463-2465, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31240468
2.
Transcription ; 10(3): 147-156, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31135261

RESUMO

Transcriptional activation by PML-RARα, an acute promyelocytic leukemia-related oncofusion protein, requires pharmacological concentrations of all-trans retinoic acid (ATRA). However, the mechanism by which the liganded PML-RARα complex leads to the formation of the preinitiation complex has been unidentified. Here we demonstrate that the Mediator subunit MED1 plays an important role in the ATRA-dependent activation of the PML-RARα-bound promoter. Luciferase reporter assays showed that PML-RARα induced significant transcription at pharmacological doses (1 µM) of ATRA; however, this was submaximal and equivalent to the level of transcription driven by intact RARα at physiological doses (1 nM) of ATRA. Transcription depended upon the interaction of PML-RARα with the two LxxLL nuclear receptor recognition motifs of MED1, and LxxLL→LxxAA mutations led to minimal transcription. Mechanistically, MED1 interacted ATRA-dependently with the RARα portion of PML-RARα through the two LxxLL motifs of MED1. These results suggest that PML-RARα initiates ATRA-induced transcription through its interaction with MED1.


Assuntos
Subunidade 1 do Complexo Mediador/metabolismo , Proteínas de Fusão Oncogênica/agonistas , Proteínas de Fusão Oncogênica/metabolismo , Ativação Transcricional/efeitos dos fármacos , Tretinoína/farmacologia , Humanos , Subunidade 1 do Complexo Mediador/química , Ligação Proteica/efeitos dos fármacos
3.
Int J Mol Sci ; 20(7)2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-30959925

RESUMO

The RUNX1-RUNX1T1 fusion is a frequent chromosomal alteration in acute myeloid leukemias (AMLs). Although RUNX1-RUNX1T1 fusion protein has pivotal roles in the development of AMLs with the fusion, RUNX1-RUNX1T1, fusion protein is difficult to target, as it lacks kinase activities. Here, we used bioinformatic tools to elucidate targetable signaling pathways in AMLs with RUNX1-RUNX1T1 fusion. After analysis of 93 AML cases from The Cancer Genome Atlas (TCGA) database, we found expression of 293 genes that correlated to the expression of the RUNX1-RUNX1T1 fusion gene. Based on these 293 genes, the cyclooxygenase (COX), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR) pathways were predicted to be specifically activated in AMLs with RUNX1-RUNX1T1 fusion. Moreover, the in vitro proliferation of AML cells with RUNX1-RUNX1T1 fusion decreased significantly more than that of AML cells without the fusion, when the pathways were inhibited pharmacologically. The results indicate that novel targetable signaling pathways could be identified by the analysis of the gene expression features of AMLs with non-targetable genetic alterations. The elucidation of specific molecular targets for AMLs that have a specific genetic alteration would promote personalized treatment of AMLs and improve clinical outcomes.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Proteína 1 Parceira de Translocação de RUNX1/metabolismo , Adulto , Linhagem Celular , Biologia Computacional , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fatores de Transcrição/metabolismo
4.
Nat Commun ; 10(1): 1695, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979898

RESUMO

Actin cytoskeleton is well-known for providing structural/mechanical support, but whether and how it regulates chromatin and cell fate reprogramming is far less clear. Here, we report that MKL1, the key transcriptional co-activator of many actin cytoskeletal genes, regulates genomic accessibility and cell fate reprogramming. The MKL1-actin pathway weakens during somatic cell reprogramming by pluripotency transcription factors. Cells that reprogram efficiently display low endogenous MKL1 and inhibition of actin polymerization promotes mature pluripotency activation. Sustained MKL1 expression at a level seen in typical fibroblasts yields excessive actin cytoskeleton, decreases nuclear volume and reduces global chromatin accessibility, stalling cells on their trajectory toward mature pluripotency. In addition, the MKL1-actin imposed block of pluripotency can be bypassed, at least partially, when the Sun2-containing linker of the nucleoskeleton and cytoskeleton (LINC) complex is inhibited. Thus, we unveil a previously unappreciated aspect of control on chromatin and cell fate reprogramming exerted by the MKL1-actin pathway.


Assuntos
Reprogramação Celular , Cromatina/química , Transativadores/metabolismo , Citoesqueleto de Actina/metabolismo , Animais , Diferenciação Celular , Núcleo Celular/metabolismo , Citoesqueleto/metabolismo , Feminino , Fibroblastos/citologia , Transferência Ressonante de Energia de Fluorescência , Genótipo , Proteínas de Fluorescência Verde/metabolismo , Masculino , Camundongos , Proteínas de Fusão Oncogênica/metabolismo , Células-Tronco Pluripotentes/citologia
5.
Brain Tumor Pathol ; 36(2): 74-83, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30929113

RESUMO

Pediatric low-grade gliomas (PLGGs) have relatively favorable prognosis and some resectable PLGGs, such as cerebellar pilocytic astrocytoma, can be cured by surgery alone. However, many PLGG cases are unresectable and some of them undergo tumor progression. Therefore, a multidisciplinary approach is necessary to treat PLGG patients. Recent genomic analysis revealed a broad genomic landscape underlying PLGG. Notably, the majority of PLGGs present MAPK pathway-associated genomic alterations and MAPK signaling-dependent tumor progression. Following preclinical evidence, many clinical trials based on molecular target therapy have been conducted on PLGG patients, some of whom exhibited durable response to target therapy. Here, we provide an overview of PLGG genetics and the evidence supporting the application of molecular target therapy in these patients.


Assuntos
Glioma/genética , Glioma/patologia , Adolescente , Astrocitoma/genética , Astrocitoma/patologia , Astrocitoma/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Glioma/terapia , Humanos , Lactente , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas B-raf
6.
Cancer Sci ; 110(6): 1897-1908, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31006167

RESUMO

Xp11.2 translocation renal cell carcinoma (Xp11 tRCC) is a rare sporadic pediatric kidney cancer caused by constitutively active TFE3 fusion proteins. Tumors in patients with Xp11 tRCC tend to recur and undergo frequent metastasis, in part due to lack of methods available to detect early-stage disease. Here we generated transgenic (Tg) mice overexpressing the human PRCC-TFE3 fusion gene in renal tubular epithelial cells, as an Xp11 tRCC mouse model. At 20 weeks of age, mice showed no histological abnormalities in kidney but by 40 weeks showed Xp11 tRCC development and related morphological and histological changes. MicroRNA (miR)-204-5p levels in urinary exosomes of 40-week-old Tg mice showing tRCC were significantly elevated compared with levels in control mice. MicroRNA-204-5p expression also significantly increased in primary renal cell carcinoma cell lines established both from Tg mouse tumors and from tumor tissue from 2 Xp11 tRCC patients. All of these lines secreted miR-204-5p-containing exosomes. Notably, we also observed increased miR-204-5p levels in urinary exosomes in 20-week-old renal PRCC-TFE3 Tg mice prior to tRCC development, and those levels were equivalent to those in 40-week-old Tg mice, suggesting that miR-204-5p increases follow expression of constitutively active TFE3 fusion proteins in renal tubular epithelial cells prior to overt tRCC development. Finally, we confirmed that miR-204-5p expression significantly increases in noncancerous human kidney cells after overexpression of a PRCC-TFE3 fusion gene. These findings suggest that miR-204-5p in urinary exosomes could be a useful biomarker for early diagnosis of patients with Xp11 tRCC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Cromossomos Humanos X/genética , Neoplasias Renais/genética , MicroRNAs/genética , Translocação Genética , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Biomarcadores Tumorais/urina , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/urina , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Exossomos/genética , Humanos , Rim/anormalidades , Rim/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/urina , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/urina , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo
7.
Nutrients ; 11(3)2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30866528

RESUMO

Τhe effect of docosahexaenoic acid (DHA, an omega-3 polyunsaturated fatty acid) upon the proliferation of EoL-1 (Eosinophilic leukemia) cell line was assessed, while additional cellular events during the antiproliferative action were recorded. DHA inhibited EoL-1 cells growth dose-dependently by inducing growth arrest at G0/1 phase of the cell cycle. After DHA addition to the cells, the expression of MYC oncogene was decreased, PTAFR-mRNA overexpression was observed which was used as a marker of differentiation, and PLA2G4A-mRNA increase was recorded. The enzymatic activities of phospholipase A2 (PLA2), a group of hydrolytic enzymes, whose action precedes and leads to PAF biosynthesis through the remodeling pathway, as well as platelet activating factor acetylhydrolase (PAFAH) which hydrolyses and deactivates PAF, were also measured. DHA had an effect on the levels of both the intracellular and secreted activities of PLA2 and PAFAH. The inflammatory cytokines IL-6 and TNF-α were also detected in high levels. In conclusion, DHA-induced EoL-1 cells differentiation was correlated with downregulation of MYC oncogene, overexpression of PTAFR and PLA2G4A-mRNAs, increase of the inflammatory cytokines production, and alteration of the enzymatic activities that regulate PAF levels. DHA is a natural substance and the understanding of its action on EoL-1 cells on molecular level could be useful in further investigation as a future therapeutic tool against F/P ⁺ hypereosinophilic syndrome.


Assuntos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Leucemia/metabolismo , Linhagem Celular Tumoral , Expressão Gênica/efeitos dos fármacos , Fosfolipases A2 do Grupo IV/genética , Fosfolipases A2 do Grupo IV/metabolismo , Humanos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Glicoproteínas da Membrana de Plaquetas/genética , Glicoproteínas da Membrana de Plaquetas/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/genética , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo
8.
Cancer Biomark ; 24(4): 383-393, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30909182

RESUMO

Cancer, a deadly disease is characterized by abnormal cell growth with the potential to invade to other parts of the body. Most cancers start due to changes at gene level that happen over a person's lifetime when DNA repair system becomes faulty. CCDC6, one of the players in DNA repair system acts as a tumor suppressor gene. It was originally identified in chimeric genes caused by chromosomal translocation involving RET proto-oncogene in some thyroid tumors. Different fusion chimers with different proto-oncogenes like RET are known for CCDC6 which hampered its function. Further, CCDC6 is recognized as a pro-apoptotic phosphoprotein, which is an ATM substrate responsive to genotoxic stress. In this article, we reviewed the published literature to characterize CCDC6 fusions with proto-oncogenes and the role of natural phytochemicals which can potentially alter CCDC6 activity and thus can prove beneficial for cancer patients.


Assuntos
Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proto-Oncogenes , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Proteínas do Citoesqueleto/química , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/química , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Relação Estrutura-Atividade
9.
Nat Commun ; 10(1): 1295, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894541

RESUMO

ABCB1 encodes Multidrug Resistance protein (MDR1), an ATP-binding cassette member involved in the cellular efflux of chemotherapeutic drugs. Here we report that ovarian and breast samples from chemotherapy treated patients are positive for multiple transcriptional fusions involving ABCB1, placing it under the control of a strong promoter while leaving its open reading frame intact. We identified 15 different transcriptional fusion partners involving ABCB1, as well as patients with multiple distinct fusion events. The partner gene selected depended on its structure, promoter strength, and chromosomal proximity to ABCB1. Fusion positivity was strongly associated with the number of lines of MDR1-substrate chemotherapy given. MDR1 inhibition in a fusion positive ovarian cancer cell line increased sensitivity to paclitaxel more than 50-fold. Convergent evolution of ABCB1 fusion is therefore frequent in chemotherapy resistant recurrent ovarian cancer. As most currently approved PARP inhibitors (PARPi) are MDR1 substrates, prior chemotherapy may precondition resistance to PARPi.


Assuntos
Neoplasias da Mama/genética , Cistadenocarcinoma Seroso/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Fusão Oncogênica/genética , Neoplasias Ovarianas/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Coortes , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Proteínas de Fusão Oncogênica/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Paclitaxel/uso terapêutico , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Regiões Promotoras Genéticas , Recidiva , Transcrição Genética
10.
Nat Commun ; 10(1): 1353, 2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30903020

RESUMO

Liposarcomas (LPSs) are a group of malignant mesenchymal tumors showing adipocytic differentiation. Here, to gain insight into the enhancer dysregulation and transcriptional addiction in this disease, we chart super-enhancer structures in both LPS tissues and cell lines. We identify a bromodomain and extraterminal (BET) protein-cooperated FUS-DDIT3 function in myxoid LPS and a BET protein-dependent core transcriptional regulatory circuitry consisting of FOSL2, MYC, and RUNX1 in de-differentiated LPS. Additionally, SNAI2 is identified as a crucial downstream target that enforces both proliferative and metastatic potentials to de-differentiated LPS cells. Genetic depletion of BET genes, core transcriptional factors, or SNAI2 mitigates consistently LPS malignancy. We also reveal a compelling susceptibility of LPS cells to BET protein degrader ARV-825. BET protein depletion confers additional advantages to circumvent acquired resistance to Trabectedin, a chemotherapy drug for LPS. Moreover, this study provides a framework for discovering and targeting of core oncogenic transcriptional programs in human cancers.


Assuntos
Lipossarcoma/genética , Proteínas de Neoplasias/metabolismo , Transcrição Genética , Animais , Azepinas/farmacologia , Sequência de Bases , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos/genética , Genoma Humano , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Fusão Oncogênica/metabolismo , Talidomida/análogos & derivados , Talidomida/farmacologia , Transcrição Genética/efeitos dos fármacos
11.
Nat Commun ; 10(1): 1459, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30926794

RESUMO

Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.


Assuntos
Linfoma de Burkitt/genética , Genoma Humano , Transcriptoma/genética , Adolescente , Processamento Alternativo/genética , Sequência de Aminoácidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Estudos de Coortes , Metilação de DNA/genética , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação INDEL/genética , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fases de Leitura Aberta/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas c-myc/genética , Translocação Genética , Sequenciamento Completo do Genoma
12.
J Cutan Pathol ; 46(6): 421-424, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30834570

RESUMO

Cutaneous syncytial myoepithelioma (CSM) is a recently recognized, histopathological variant of myoepithelial (ME) tumors of the skin. It is characterized by a syncytial arrangement of spindled, ovoid, and/or epithelioid cells forming a well-circumscribed, unencapsulated dermal nodule. There is a paucity of intervening stroma, and absent duct or gland formation. Strong immunohistochemical staining for S100 and epithelial membrane antigen (EMA) has been described, while cytokeratin expression has been uncommon. The majority of CSMs harbor a rearrangement involving the EWSR1 gene. Although various fusion partner genes have been discovered in ME tumors at other anatomic sites, none has yet been described in CSM. We present a case of CSM represented clinically by a papule on the mid-upper back of a healthy 44-year-old female. It exhibited morphological and immunohistochemical features of a CSM with strong, diffuse S100 and alpha-actin expression, and focal positivity for EMA and cytokeratin AE1/AE3. Fluorescence in-situ hybridization showed an EWSR1 gene rearrangement. Massively parallel next-generation RNA sequencing revealed PBX3 as the fusion partner. The EWSR1-PBX3 gene fusion has been previously identified in three cases of ME tumors of bone and soft tissue, and in a case of retroperitoneal leiomyoma. This is the first report of an EWSR1-PBX3 fusion in CSM.


Assuntos
Biomarcadores Tumorais , Proteínas de Homeodomínio , Mioepitelioma , Proteínas de Fusão Oncogênica , Proteínas Proto-Oncogênicas , Proteína EWS de Ligação a RNA , Neoplasias Cutâneas , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Queratinas/genética , Queratinas/metabolismo , Mioepitelioma/genética , Mioepitelioma/metabolismo , Mioepitelioma/patologia , Fusão Oncogênica , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
14.
Ann Hematol ; 98(5): 1149-1157, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30759270

RESUMO

t(8;16)(p11.2;p13.3)/KAT6A-CREBBP is a rare recurrent cytogenetic abnormality associated with acute myeloid leukemia (AML). We report 15 cases with t(8;16)(p11.2;p13.3). All patients were adult and had AML: 13 women and 2 men, with a median age of 50 years. Ten patients had a history of malignancy and received cytotoxic therapies before therapy-related AML (t-AML), and five patients had de novo AML. All cases of AML showed monoblastic (n = 12) or myelomonocytic (n = 3) differentiation. Hemophagocytosis was observed in seven patients. All patients had t(8;16) in the stemline: seven had t(8;16) as the sole abnormality, two had one additional abnormality, and six had a complex karyotype. KAT6A/CREBBP rearrangement was confirmed by fluorescence in situ hybridization in 13 patients who had material available for analysis. All patients received induction chemotherapy, and 11 achieved complete remission after first induction. At the time of last follow-up, nine patients (eight t-AML and one de novo AML) died and six were alive, with a median overall survival of 18.2 months. The patients with de novo AML and/or patients with non-complex karyotype showed an "undefined" overall survival. We conclude that t(8;16)(p11.2;p13.3) commonly exhibits monoblastic or myelomonocytic differentiation and commonly arises in patients with a history of cancer treated with cytotoxic therapies. Patients with de novo AML with t(8;16) or t-AML with t(8;16) without adverse prognostic factors (e.g., complex karyotype) have a good outcome.


Assuntos
Proteína de Ligação a CREB , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 8 , Histona Acetiltransferases , Leucemia Mieloide Aguda , Proteínas de Fusão Oncogênica , Translocação Genética , Adulto , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 16/metabolismo , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 8/metabolismo , Feminino , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Estudos Retrospectivos
15.
Int J Oncol ; 54(3): 981-990, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628662

RESUMO

The immunoglobulin enhancer­binding factor/hepatic leukemia factor (E2A­HLF) oncogenic fusion gene, generated by t(17;19)(q22;p13) translocation in childhood B­cell acute lymphoblastic leukemia with a very poor prognosis, encodes a chimeric transcription factor in which the transactivation domains of E2A are fused to the DNA­binding and dimerization domain of HLF. E2A­HLF has been demonstrated to have an anti­apoptotic effect. However, the molecular mechanism underlying E2A­HLF­mediated leukemogenesis remains unclear. The present study identified EYA transcriptional coactivator and phosphatase 2 (Eya2), the forced expression of which is known to immortalize mouse hematopoietic stem/progenitor cells (HSPCs), as a direct target molecule downstream of E2A­HLF. E2A­HLF­immortalized mouse HSPCs expressed Eya2 at a high level in the aberrant self­renewal program. Chromatin immunoprecipitation­quantitative polymerase chain reaction and a reporter assay revealed that E2A­HLF enhanced the Eya2 expression by binding to the promoter region containing the E2A­HLF­binding consensus sequence. Eya2 knockdown in E2A­HLF­immortalized cells resulted in reduced colony­forming efficiency. These results suggest a critical role of Eya2 in E2A­HLF­mediated leukemogenesis.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células-Tronco Hematopoéticas/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Transformação Celular Neoplásica/metabolismo , Técnicas de Silenciamento de Genes , Células-Tronco Hematopoéticas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Regiões Promotoras Genéticas , Proteínas Tirosina Fosfatases/antagonistas & inibidores , RNA Interferente Pequeno , Regulação para Cima
17.
Int J Hematol ; 109(4): 477-482, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30689137

RESUMO

ETV6-RUNX1-positive B precursor acute lymphoblastic leukemia (B-ALL) is a common subtype of pediatric B-ALL that has shown excellent outcomes in contemporary clinical trials for pediatric B-ALL. Examinations of the possibility of reducing therapeutic intensity may thus be explored. This prospective study examined outcomes in 205 pediatric patients with ETV6-RUNX1-positive B-ALL uniformly treated following the Japan Association of Childhood Leukemia Study Group (JACLS) ALL-02 protocol. The JACLS ALL-02 protocol does not employ minimal residual disease detected by polymerase chain reaction (PCR-MRD)-based risk stratification; however, 4-year event-free survival (EFS) and overall survival (OS) were 94.4 ± 1.6 and 97.5 ± 1.1%, respectively. In particular, 92 of 205 (44.9%) patients were successfully treated with a less intensive regimen involving only two cycles of high dose methotrexate and one course of re-induction therapy comprising vincristine, L-asparaginase (L-asp), pirarubicin, and prednisolone. Multivariate analysis revealed that discontinuation of L-asp and poor response to prednisolone was, respectively, associated with poor EFS (HR 6.3; 95% CI 1.3-27.0) and OS (HR 17.5; 95% CI 2.3-130), suggesting that the majority of ETV6-RUNX1-positive B-ALL cases may be cured by a less-intensive chemotherapy regimen if the risk stratification system including PCR-MRD monitoring and insufficient use of L-asp is avoided.


Assuntos
Asparaginase/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prednisolona/administração & dosagem , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Medição de Risco , Taxa de Sobrevida
18.
Int J Cancer ; 144(1): 190-199, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30255938

RESUMO

Tyrosine kinase inhibitors (TKI) have improved prognosis in metastatic anaplastic lymphoma kinase (ALK)-driven lung adenocarcinoma, but patient outcomes vary widely. We retrospectively analyzed the clinical course of all cases with assessable baseline TP53 status and/or ALK fusion variant treated at our institutions (n = 102). TP53 mutations were present in 17/87 (20%) and the echinoderm microtubule-associated protein-like 4 (EML4)-ALK variant 3 (V3) in 41/92 (45%) patients. The number of metastatic sites at diagnosis was affected more by the presence of V3 than by TP53 mutations, and highest with both factors (mean 5.3, p < 0.001). Under treatment with ALK TKI, progression-free survival (PFS) was shorter with either TP53 mutations or V3, while double positive cases appeared to have an even higher risk (hazard ratio [HR] = 2.9, p = 0.015). The negative effect of V3 on PFS of TKI-treated patients was strong already in the first line (HR = 2.5, p = 0.037) and decreased subsequently, whereas a trend for PFS impairment under first-line TKI by TP53 mutations became stronger and statistically significant only when considering all treatment lines together. Overall survival was impaired more by TP53 mutations (HR = 4.9, p = 0.003) than by V3 (HR = 2.4, p = 0.018), while patients with TP53 mutated V3-driven tumors carried the highest risk of death (HR = 9.1, p = 0.02). Thus, TP53 mutations and V3 are independently associated with enhanced metastatic spread, shorter TKI responses and inferior overall survival in ALK+ lung adenocarcinoma. Both markers could assist selection of cases for more aggressive management and guide development of novel therapeutic strategies. In combination, they define a patient subset with very poor outcome.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Mutação , Proteínas de Fusão Oncogênica/genética , Proteína Supressora de Tumor p53/genética , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/metabolismo , Avaliação de Resultados (Cuidados de Saúde) , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Proteína Supressora de Tumor p53/metabolismo
19.
Proc Natl Acad Sci U S A ; 116(3): 890-899, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30593567

RESUMO

The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 20% of acute myeloid leukemia (AML) cases. In leukemic cells, AML1-ETO resides in and functions through a stable protein complex, AML1-ETO-containing transcription factor complex (AETFC), that contains multiple transcription (co)factors. Among these AETFC components, HEB and E2A, two members of the ubiquitously expressed E proteins, directly interact with AML1-ETO, confer new DNA-binding capacity to AETFC, and are essential for leukemogenesis. However, the third E protein, E2-2, is specifically silenced in AML1-ETO-expressing leukemic cells, suggesting E2-2 as a negative factor of leukemogenesis. Indeed, ectopic expression of E2-2 selectively inhibits the growth of AML1-ETO-expressing leukemic cells, and this inhibition requires the bHLH DNA-binding domain. RNA-seq and ChIP-seq analyses reveal that, despite some overlap, the three E proteins differentially regulate many target genes. In particular, studies show that E2-2 both redistributes AETFC to, and activates, some genes associated with dendritic cell differentiation and represses MYC target genes. In AML patients, the expression of E2-2 is relatively lower in the t(8;21) subtype, and an E2-2 target gene, THPO, is identified as a potential predictor of relapse. In a mouse model of human t(8;21) leukemia, E2-2 suppression accelerates leukemogenesis. Taken together, these results reveal that, in contrast to HEB and E2A, which facilitate AML1-ETO-mediated leukemogenesis, E2-2 compromises the function of AETFC and negatively regulates leukemogenesis. The three E proteins thus define a heterogeneity of AETFC, which improves our understanding of the precise mechanism of leukemogenesis and assists development of diagnostic/therapeutic strategies.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Leucemia Mieloide Aguda/etiologia , Proteínas de Fusão Oncogênica/metabolismo , Proteína 1 Parceira de Translocação de RUNX1/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Humanos , Leucemia Mieloide Aguda/metabolismo , Recidiva
20.
Oncol Rep ; 41(3): 2027-2040, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30569130

RESUMO

The t(8;21) translocation is one of the most frequent chromosome abnormalities associated with acute myeloid leukaemia (AML). This abberation deregulates numerous molecular pathways including the ERK signalling pathway among others. Therefore, the aim of the present study was to investigate the gene expression patterns following siRNA­mediated suppression of RUNX1­RUNX1T1 and MAPK1 in Kasumi­1 and SKNO­1 cells and to determine the differentially expressed genes in enriched biological pathways. BeadChip microarray and gene ontology analysis revealed that RUNX1­RUNX1T1 and MAPK1 suppression reduced the proliferation rate of the t(8;21) cells with deregulated expression of several classical positive regulator genes that are otherwise known to enhance cell proliferation. RUNX1­RUNX1T1 suppression exerted an anti­apoptotic effect through the overexpression of BCL2, BIRC3 and CFLAR genes, while MAPK1 suppression induced apopotosis in t(8;21) cells by the apoptotic mitochondrial changes stimulated by the activity of upregulated TP53 and TNFSF10, and downregulated JUN gene. RUNX1­RUNX1T1 suppression supported myeloid differentiation by the differential expression of CEBPA, CEBPE, ID2, JMJD6, IKZF1, CBFB, KIT and CDK6, while MAPK1 depletion inhibited the differentiation of t(8;21) cells by elevated expression of ADA and downregulation of JUN. RUNX1­RUNX1T1 and MAPK1 depletion induced cell cycle arrest at the G0/G1 phase. Accumulation of cells in the G1 phase was largely the result of downregulated expression of TBRG4, CCNE2, FOXO4, CDK6, ING4, IL8, MAD2L1 and CCNG2 in the case of RUNX1­RUNX1T1 depletion and increased expression of RASSF1, FBXO6, DADD45A and P53 in the case of MAPK1 depletion. Taken together, the current results demonstrate that MAPK1 promotes myeloid cell proliferation and differentiation simultaneously by cell cycle progression while suppresing apoptosis.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Sistema de Sinalização das MAP Quinases/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteínas de Fusão Oncogênica/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Translocação Genética , Apoptose/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Perfilação da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/patologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas de Fusão Oncogênica/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteína 1 Parceira de Translocação de RUNX1/metabolismo
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