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3.
Exp Hematol ; 76: 60-66.e2, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31369790

RESUMO

Exosomes are virus-size membrane-bound vesicles of endocytic origin present in all body fluids. Plasma of AML patients is significantly enriched in exosomes, which carry a cargo of immunosuppressive molecules and deliver them to recipient immune cells, suppressing their functions. However, whether these exosomes originate from leukemic blasts or from various normal cells in the bone marrow or other tissues is unknown. In the current study, we developed an AML PDX model in mice and studied the molecular cargo and immune cell effects of the AML PDX exosomes in parallel with the exosomes from plasma of the corresponding AML patients. Fully engrafted AML PDX mice produced exosomes with characteristics similar to those of exosomes isolated from plasma of the AML patients who had donated the cells for engraftment. The engrafted leukemic cells produced exosomes that carried human proteins and leukemia-associated antigens, confirming the human origin of these exosomes. Furthermore, the AML-derived exosomes carried immunosuppressive proteins responsible for immune cell dysfunctions. Our studies of exosomes in AML PDX mice serve as a proof of concept that AML blasts are the source of immunosuppressive exosomes with a molecular profile that mimics the content and functions of the parental cells.


Assuntos
Exossomos , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/metabolismo , Evasão Tumoral/fisiologia , Idoso , Animais , Antígenos de Neoplasias/sangue , Feminino , Xenoenxertos , Humanos , Leucemia Mielomonocítica Aguda/patologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Transplante de Neoplasias , Subpopulações de Linfócitos T/imunologia
4.
Anticancer Res ; 39(8): 4329-4332, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366525

RESUMO

BACKGROUND/AIM: Acute myeloid leukemia is well characterized by chromosomal aberrations that correspond to various subtypes of acute leukemias. The t(8;21)(q22;q22) is a frequent chromosomal abnormality strongly associated with acute myeloblastic leukemia with maturation (AML-M2), but is rarely associated with other subtypes. Translocation involving a third chromosome could produce new genetic rearrangements that lead to leukemogenesis. PATIENTS AND METHODS: Conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) were performed to identify the karyotype. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to detect the AML1/ETO transcript. RESULTS/CONCLUSION: We herein report a novel rearrangement with a three-way translocation involving chromosomes 8, 21 and another unknown chromosome, in an 83-year-old female patient diagnosed as AML-M4, with an ALM1/ETO negative transcript. This is an uncommon case of AML-M4 with three-way translocation in a new variant of t(8;21) acute myeloid leukaemia. The detailed mechanism of different phenotype expression is unclear. Further study is needed to identify the leukemogenetic transformation resulting from t(8;21) translocation.


Assuntos
Análise Citogenética , Cariótipo , Leucemia Mielomonocítica Aguda/genética , Translocação Genética/genética , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Cariotipagem/métodos , Leucemia Mielomonocítica Aguda/diagnóstico , Leucemia Mielomonocítica Aguda/patologia
5.
BMJ Case Rep ; 12(1)2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642851

RESUMO

A 19-year-old woman presented to the outpatient department with occasional ocular pain and redness and a perilimbal mass, which she noticed 5 months ago in her left eye. She had no systemic complaints. Ultrasound biomicroscopy of the mass showed a hypoechoic lesion with uniform reflectivity. The patient underwent an excision biopsy and a histopathological analysis revealed features suggestive of a granulocytic sarcoma/myeloid sarcoma. Further haematopathological evaluation confirmed concurrent acute myeloid (myelomonocytic) leukaemia French American British classification M4. There was complete remission of the ocular surface lesion and leukaemia with systemic chemotherapy. At the last follow-up of 18 months post-treatment the patient is free of disease.


Assuntos
Dor Ocular/diagnóstico , Sarcoma Mieloide/patologia , Sarcoma Mieloide/cirurgia , Assistência ao Convalescente , Biópsia , Tratamento Farmacológico/métodos , Dor Ocular/etiologia , Dor Ocular/patologia , Feminino , Humanos , Leucemia Mielomonocítica Aguda/patologia , Microscopia Acústica/métodos , Indução de Remissão , Sarcoma Mieloide/diagnóstico por imagem , Sarcoma Mieloide/tratamento farmacológico , Resultado do Tratamento , Adulto Jovem
6.
Artif Cells Nanomed Biotechnol ; 46(8): 1792-1798, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29113504

RESUMO

Acute myeloid leukaemia (AML) is a genetically heterogeneous, severe and rapidly progressing disease triggered by blocking granulocyte or monocyte differentiation and maturation. Overexpression of myeloid cell leukaemia-1 (Mcl-1) and Survivin is associated with drug resistance, tumour progression and inhibition of apoptotic mechanisms in leukaemia and several cancers. In the present study, we examined the combined effect of etoposide and dual siRNA-mediated silencing of Mcl-1 and Survivin on U-937 AML cells. The AML cells were co-transfected with Mcl-1 and Survivin-specific siRNAs and genes silencing were confirmed by quantitative real-time PCR and Western blotting. Subsequently, MTT assay was used for the evaluation of cytotoxic effects by dual siRNA and etoposide on their own and in combination. For the studying of apoptosis, DNA-histone ELISA and annexin-V/FITC assays were performed. Co-transfection of Mcl-1 and Survivin siRNA significantly blocked their expression at the mRNA and protein levels, leading to the induction of apoptosis and strong inhibition of growth (p < .05). Besides, combined treatment of etoposide with Mcl-1 and Survivin siRNAs co-transfection leads to synergistically enhance etoposide-induced cytotoxic and apoptotic effects (p < .05). The results showed that Mcl-1 and Survivin play a major role in the U937 cells survival and their resistance relative to etoposide. Thus, Mcl-1 and Survivin can be considered as promising molecular targets for the treatment of AML. The combination treatment with etoposide, and siRNA-mediated silencing of corresponding genes may be a novel strategy in chemoresistance AML treatment.


Assuntos
Apoptose , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/farmacologia , Inativação Gênica , Leucemia Mielomonocítica Aguda/terapia , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , RNA Interferente Pequeno/farmacologia , Survivina/antagonistas & inibidores , Humanos , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/metabolismo , Leucemia Mielomonocítica Aguda/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/biossíntese , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , RNA Interferente Pequeno/genética , Survivina/biossíntese , Survivina/genética , Células U937
10.
Oncogene ; 35(15): 1965-76, 2016 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-26148230

RESUMO

The ETS transcription factor ERG has been implicated as a major regulator of both normal and aberrant hematopoiesis. In acute myeloid leukemias harboring t(16;21), ERG function is deregulated due to a fusion with FUS/TLS resulting in the expression of a FUS-ERG oncofusion protein. How this oncofusion protein deregulates the normal ERG transcription program is unclear. Here, we show that FUS-ERG acts in the context of a heptad of proteins (ERG, FLI1, GATA2, LYL1, LMO2, RUNX1 and TAL1) central to proper expression of genes involved in maintaining a stem cell hematopoietic phenotype. Moreover, in t(16;21) FUS-ERG co-occupies genomic regions bound by the nuclear receptor heterodimer RXR:RARA inhibiting target gene expression and interfering with hematopoietic differentiation. All-trans retinoic acid treatment of t(16;21) cells as well as FUS-ERG knockdown alleviate the myeloid-differentiation block. Together, the results suggest that FUS-ERG acts as a transcriptional repressor of the retinoic acid signaling pathway.


Assuntos
Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 21/genética , Regulação Neoplásica da Expressão Gênica/genética , Hematopoese/fisiologia , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Aguda/genética , Proteínas de Neoplasias/fisiologia , Proteínas de Fusão Oncogênica/fisiologia , Proteína FUS de Ligação a RNA/fisiologia , Transdução de Sinais/fisiologia , Translocação Genética , Tretinoína/fisiologia , Motivos de Aminoácidos , Linhagem Celular Tumoral , Cromossomos Humanos Par 16/ultraestrutura , Cromossomos Humanos Par 21/ultraestrutura , Dimerização , Elementos Facilitadores Genéticos , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/fisiopatologia , Leucemia Mielomonocítica Aguda/patologia , Leucemia Mielomonocítica Aguda/fisiopatologia , Complexos Multiproteicos , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/patologia , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Regiões Promotoras Genéticas , Ligação Proteica , Mapeamento de Interação de Proteínas , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , Proteína FUS de Ligação a RNA/antagonistas & inibidores , Proteína FUS de Ligação a RNA/genética , Receptores do Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico , Receptores X Retinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Tretinoína/farmacologia , Células U937
11.
Blood ; 127(11): 1449-58, 2016 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-26712908

RESUMO

Patients with relapsed acute myeloid leukemia (AML) have limited therapeutic options. Vesicular stomatitis virus (VSV)-interferon ß (IFNß)-sodium iodide symporter (NIS) is an oncolytic VSV encoding IFNß and the NIS reporter. Syngeneic AML C1498 tumors responded to IV therapy with VSV-murine IFNß (mIFNß)-NIS in a dose-dependent manner. Imaging for NIS expression showed robust virus infection within the tumors. Virus infection did not increase programmed death ligand 1 (PD-L1) on tumor cells. Combining VSV-mIFNß-NIS with anti-PD-L1 antibody (Ab) therapy enhanced antitumor activity compared with treatment with virus alone or Ab alone; this enhancement was not significant at higher VSV-mIFNß-NIS doses. Systemic VSV therapy reduced systemic C1498-green fluorescent protein (GFP) tumor burden in the blood, bone marrow, spleen, and liver of mice with AML. Combination VSV-mIFNß-NIS and anti-PD-L1 Ab therapy significantly enhanced the survival of these mice with no evidence of toxicity, compared with isotype control, anti-PD-L1, or virus alone. There was an increase in tumor-infiltrating CD4 and CD8 cells. Single-agent VSV-mIFNß-NIS virotherapy induced both VSV-specific and GFP-specific CD8 T cells as determined by IFN-γ enzyme-linked immunospot, pentamer, and intracellular IFN-γ staining assays. Both of these responses were further enhanced by addition of anti-PD-L1 Ab. Depletion of CD8 or natural killer cells, but not CD4 cells, resulted in loss of antitumor activity in the VSV/anti-PD-L1 group. Clinical samples from chronic myelomonocytic leukemia and acute myelomonocytic leukemia appear to be especially susceptible to VSV. Overall, our studies show that oncolytic virotherapy combined with immune checkpoint blockade is a promising approach to AML therapy.


Assuntos
Antígeno B7-H1/imunologia , Imunoterapia , Leucemia Mieloide Aguda/terapia , Terapia Viral Oncolítica , Vírus da Estomatite Vesicular Indiana/fisiologia , Animais , Antígeno B7-H1/análise , Medula Óssea/patologia , Linhagem Celular Tumoral , Terapia Combinada , Feminino , Genes Reporter , Vetores Genéticos/genética , Proteínas de Fluorescência Verde/genética , Humanos , Interferon beta/genética , Lentivirus/genética , Leucemia Mieloide Aguda/diagnóstico por imagem , Leucemia Mielomonocítica Aguda/patologia , Leucemia Mielomonocítica Crônica/patologia , Leucócitos Mononucleares/patologia , Subpopulações de Linfócitos/imunologia , Linfócitos do Interstício Tumoral/química , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Neoplasias/análise , Cintilografia , Simportadores/genética , Carga Tumoral
12.
J Biol Regul Homeost Agents ; 29(2): 395-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26122228

RESUMO

Tumor protein p53 encoded by the TP53 gene in humans is known as a cancer biomarker in patients diagnosed with cancer, and it plays an essential role in apoptosis, genomic stability, and inhibition of angiogenesis. Cancer therapies with common chemotherapy methods are effective, as known, but have some side effects. Berberis vulgaris is traditionally administrated as a cancer drug. The current research aims to evaluate p53 as a biomarker in WEHI-3 cell line and to demonstrate the Berberis vulgaris fruit crude extract (BVFCE) as a new anticancer drug. For this purpose, we evaluated the effect of BVFCE in different concentrations against WEHI-3cell line in vitro and determined the quantitative level of p53 gene in the treated WEHI-3 cells. The results demonstrated that even at only 1 mg/ml concentration of Berberis vulgaris crude extract, there was a low level of p53 biomarker expression on WEHI-3 cells in comparison with doxorubicin. Therefore, the current study suggests BVFCE as a reliable anti-leukaemic drug and candidate for anticancer therapy. However, further investigation need be carried out to confirm its efficiency in vivo.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Berberis/química , Frutas/química , Leucemia Experimental/patologia , Leucemia Mielomonocítica Aguda/patologia , Fitoterapia , Extratos Vegetais/farmacologia , Células 3T3 , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Genes p53 , Concentração Inibidora 50 , Camundongos , Proteína Supressora de Tumor p53/análise
15.
Exp Hematol ; 43(7): 524-33.e1, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25846811

RESUMO

Adenosine monophosphate-activated protein kinase (AMPK) is a sensor for cellular energy status. When the cellular energy level is decreased, AMPK is activated and functions to suppress energy-consuming processes, including protein synthesis. Recently, AMPK has received attention as an attractive molecular target for cancer therapy. Several studies have revealed that the activation of AMPK by chemical stimulators, such as metformin, induces apoptosis in a variety of hematologic malignant cells. From another perspective, these results suggest that the function of AMPK is impaired in hematologic tumor cells. However, the precise mechanisms by which this impairment occurs are not well understood. In melanoma cells, oncogenic BRAF constitutively activates the extracellular signal-regulated kinase (ERK) pathway and phosphorylates liver kinase B1, an upstream activator of 5' adenosine monophosphate-activated protein kinase (AMPK), resulting in the inactivation of liver kinase B1 and AMPK. In this study, we analyzed whether ERK is involved in the suppression of AMPK activity using established and primary human leukemia cells. We found an inverse correlation between the intensity of ERK activity and the degree of AMPK activation after stimulation with either glucose deprivation or metformin. We also found that the inhibition of ERK activity by U0126 restored AMPK activation after metformin treatment. Furthermore, a combined treatment with metformin and U0126 enhanced the antileukemic activity of metformin. Importantly, metformin induced ERK activation by suppressing the protein levels of dual specificity phosphatase 6, a negative regulator of ERK. This crosstalk between AMPK and ERK could diminish the antileukemic activity of metformin. Taken together, our present observations suggest a novel therapeutic strategy for improving the efficacy of metformin in treating leukemia.


Assuntos
Proteínas Quinases Ativadas por AMP/fisiologia , Leucemia Mieloide Aguda/patologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteína Quinase 1 Ativada por Mitógeno/fisiologia , Proteína Quinase 3 Ativada por Mitógeno/fisiologia , Proteínas de Neoplasias/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Quinases Ativadas por AMP/genética , Adulto , Idoso , Antineoplásicos/farmacologia , Apoptose , Butadienos/farmacologia , Linhagem Celular Tumoral , Interações Medicamentosas , Fosfatase 6 de Especificidade Dupla/fisiologia , Ativação Enzimática , Retroalimentação Fisiológica , Feminino , Glucose/farmacologia , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mielomonocítica Aguda/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metformina/farmacologia , Pessoa de Meia-Idade , Nitrilos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas
16.
Sci Rep ; 5: 8283, 2015 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-25655563

RESUMO

We present a system-wide transcriptional network structure that controls cell types in the context of expression pattern transitions that correspond to cell type transitions. Co-expression based analyses uncovered a system-wide, ladder-like transcription factor cluster structure composed of nearly 1,600 transcription factors in a human transcriptional network. Computer simulations based on a transcriptional regulatory model deduced from the system-wide, ladder-like transcription factor cluster structure reproduced expression pattern transitions when human THP-1 myelomonocytic leukaemia cells cease proliferation and differentiate under phorbol myristate acetate stimulation. The behaviour of MYC, a reprogramming Yamanaka factor that was suggested to be essential for induced pluripotent stem cells during dedifferentiation, could be interpreted based on the transcriptional regulation predicted by the system-wide, ladder-like transcription factor cluster structure. This study introduces a novel system-wide structure to transcriptional networks that provides new insights into network topology.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/patologia , Modelos Biológicos , Ésteres de Forbol/farmacologia , Transcrição Genética , Linhagem Celular Tumoral , Análise por Conglomerados , Biologia Computacional/métodos , Humanos
18.
Ann Hematol ; 94(2): 211-21, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25241285

RESUMO

Recently, mutations of the GATA binding protein 2 (GATA2) gene were identified in acute myeloid leukemia (AML) patients with CEBPA double mutations (CEBPA (double-mut)), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, 14 different missense GATA2 mutations, which were all clustered in the highly conserved N-terminal zinc finger 1 domain, were identified in 27.4, 6.7, and 1 % of patients with CEBPA (double-mut), CEBPA (single-mut), and CEBPA wild type, respectively. All but one patient with GATA2 mutation had concurrent CEBPA mutation. GATA2 mutations were closely associated with younger age, FAB M1 subtype, intermediate-risk cytogenetics, expression of HLA-DR, CD7, CD15, or CD34 on leukemic cells, and CEBPA mutation, but negatively associated with FAB M4 subtype, favorable-risk cytogenetics, and NPM1 mutation. Patients with GATA2 mutation had significantly better overall survival and relapse-free survival than those without GATA2 mutation. Sequential analysis showed that the original GATA2 mutations might be lost during disease progression in GATA2-mutated patients, while novel GATA2 mutations might be acquired at relapse in GATA2-wild patients. In conclusion, AML patients with GATA2 mutations had distinct clinic-biological features and a favorable prognosis. GATA2 mutations might be lost or acquired at disease progression, implying that it was a second hit in the leukemogenesis of AML, especially those with CEBPA mutation.


Assuntos
Fator de Transcrição GATA2/genética , Leucemia Mieloide/genética , Mutação , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Aberrações Cromossômicas , Progressão da Doença , Seguimentos , Genótipo , Humanos , Estimativa de Kaplan-Meier , Cariótipo , Leucemia Eritroblástica Aguda/tratamento farmacológico , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/patologia , Leucemia Monocítica Aguda/tratamento farmacológico , Leucemia Monocítica Aguda/genética , Leucemia Monocítica Aguda/patologia , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/patologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/patologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Adulto Jovem
19.
Anticancer Drugs ; 26(4): 410-21, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25535978

RESUMO

PP242 is a novel dual mammalian target of rapamycin (mTOR) inhibitor that simultaneously inhibits mTORC1 and mTORC2, and its antileukemia effect has been sufficiently investigated here. The human acute leukemia cell lines and primary blasts were treated with PP242 alone or in combination with daunorubicin (DNR). Cell proliferation was examined using an MTT assay. The phosphorylation expression of the Akt/mTORC1/eIF4E signaling pathway was assessed by western blot analysis. The assembly of the eIF4F translation initiation complex was examined using a 7-methyl-guanosine cap affinity assay. PP242 significantly induced cytotoxicity in human acute leukemia cells, especially in combination with DNR. The phosphorylation levels of eIF4E (p-eIF4E) at Ser209 influence the antileukemia roles of PP242. As expected, the antiproliferative effects of PP242 on leukemia cells with low p-eIF4E expression, such as the acute promyelocytic leukemia NB4 cell line and AML-M3 primary blasts, were poor. Surprisingly, the effects of PP242 in leukemia cells with high p-eIF4E expression, such as the acute myelomonocytic leukemia THP-1 cell line and M4-M5 primary blasts, were also weak. In contrast, PP242 exerted a significant antiproliferative effect in the Ph+ acute lymphoblastic leukemia SUP-B15 cell line and the mantle cell lymphoma JEKO-1 cell line, which had intermediate p-eIF4E levels. PP242 inhibited the translation of the antiapoptotic protein Mcl-1 by downregulating the Akt/mTORC1/eIF4E signaling pathway. More importantly, DNR activated the Akt/mTORC1/eIF4E signaling pathway, whereas PP242 effectively eliminated this deleterious side effect of DNR and synergistically enhanced the anticancer ability of DNR treatment. PP242, especially in combination with DNR, exerts significant antileukemia effects.


Assuntos
Antineoplásicos/farmacologia , Daunorrubicina/farmacologia , Indóis/farmacologia , Leucemia/patologia , Purinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Fator de Iniciação 4E em Eucariotos/metabolismo , Humanos , Leucemia Mielomonocítica Aguda/patologia , Leucemia Promielocítica Aguda/patologia , Linfoma de Célula do Manto/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Complexos Multiproteicos/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
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