Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.140
Filtrar
1.
Hematol Oncol ; 38(1): 22-33, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31487068

RESUMO

Acute lymphoblastic leukemia (ALL) represents a heterogeneous group of hematologic malignancies, and it is normally characterized by an aberrant proliferation of immature lymphoid cells. Moreover, dysregulation of multiple signaling pathways that normally regulate cellular transcription, growth, translation, and proliferation is frequently encountered in this malignancy. ALL is the most frequent tumor in childhood, and adult ALL patients still correlate with poor survival. This review focuses on modern therapies in ALL that move beyond standard chemotherapy, with a particular emphasis on immunotherapeutic approaches as new treatment strategies. Bi-specific T-cell Engagers (BiTE) antibodies, the chimeric antigen receptor (CAR)-T cells, or CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats [CRISPR]-associated nuclease 9) represent other new innovative approaches for this disease. Target and tailored therapy could make the difference in previously untreatable cases, i.e., precision and personalized medicine. Clinical trials will help to select the most efficient novel therapies in ALL management and to integrate them with existing treatments to achieve durable cures.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Terapia de Alvo Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Animais , Biomarcadores Tumorais/metabolismo , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Prognóstico
3.
Anticancer Res ; 39(10): 5531-5539, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570447

RESUMO

BACKGROUND: Possible correlations between the expression of immune checkpoint molecules and prognosis in childhood acute leukemia were investigated. MATERIALS AND METHODS: The expression of programmed-death 1 (PD1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and B- and T-lymphocyte attenuator (BTLA) was determined by flow cytometry on peripheral αß+ and γδ+ T-cells from patients with newly diagnosed acute lymphoblastic leukemia (ALL) (n=9) or acute myeloid leukemia (AML) (n=12), and from healthy volunteers (n=7). The expression of programmed-death ligand 1 (PD-L1), B7-1, B7-2, human leukocyte antigen-ABC (HLA-ABC), and herpesvirus-entry mediator (HVEM) ligands was determined on leukemia blasts. RESULTS: PD1 expression on αß+ and γδ+ T-cells was significantly higher in patients with ALL than in those with AML (p=0.0019 and 0.0239, respectively). CTLA-4 expression was moderately higher on αß+ and γδ+ T-cells in ALL (p=0.077 and 0.077, respectively), whereas HLA-ABC expression was significantly higher in AML blast cells (p=0.0182). The expression of CTLA-4 on γδ+ T-cells and the B7-2 ligand on blasts was higher in patients with high-risk ALL (p=0.02 and 0.02, respectively). In AML, PD1 expression on αß+ T-cells was higher in the intermediate-risk group (p=0.05), whereas HVEM expression was significantly higher in the low-risk group (p=0.02). Expression of CTLA-4 on γδ+ T-cells and PD-L1 on blasts were both associated with poor relapse-free survival outcomes in ALL (p=0.049). CONCLUSION: The higher expression of immune checkpoint molecules, in particular, CTLA-4 and PD-L1 are associated with a poorer prognosis in ALL, suggesting that selective use of the immune checkpoint blockade might improve the clinical outcomes in patients with ALL.


Assuntos
Leucemia/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Linfócitos T/imunologia , Doença Aguda , Adolescente , Adulto , Antígeno B7-H1/metabolismo , Antígeno CTLA-4/metabolismo , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Ligantes , Masculino , Pessoa de Meia-Idade , Recidiva , Adulto Jovem
4.
Blood ; 134(17): 1415-1429, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31501154

RESUMO

We investigated and modeled the mesenchymal stromal cell (MSC) niche in adult acute lymphoblastic leukemia (ALL). We used gene expression profiling, cytokine/chemokine quantification, flow cytometry, and a variety of imaging techniques to show that MSCs, directly isolated from the primary bone marrow specimens of patients with ALL, frequently adopted an activated, cancer-associated fibroblast phenotype. Normal, primary human MSCs and the MSC cell line HS27a both were activated de novo, when exposed to the reactive oxygen species (ROS)-inducing chemotherapy agents cytarabine (AraC) and daunorubicin (DNR), a phenomenon blocked by the antioxidant N-acetyl cysteine. Chemotherapy-activated HS27a cells were functionally evaluated in a coculture model with ALL targets. Activated MSCs prevented therapy-induced apoptosis and death in ALL targets, via mitochondrial transfer through tunneling nanotubes (TNTs). Reduction of mitochondrial transfer by selective mitochondrial depletion or interference with TNT formation by microtubule inhibitors, such as vincristine (VCR), prevented the "rescue" function of activated MSCs. Corticosteroids, also a mainstay of ALL therapy, prevented the activation of MSCs. We also demonstrated that AraC (but not VCR) induced activation of MSCs, mitochondrial transfer, and mitochondrial mass increase in a murine NSG model of disseminated SEM cell-derived ALL, wherein CD19+ cells closely associated with nestin+ MSCs after AraC, but not in the other conditions. Our data propose a readily clinically exploitable mechanism for improving treatment of ALL, in which traditional ROS-inducing chemotherapies are often ineffective at eradicating residual disease, despite efficiently killing the bulk population.


Assuntos
Antineoplásicos/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto , Idoso , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Células Cultivadas , Técnicas de Cocultura , Citarabina/farmacologia , Citarabina/uso terapêutico , Daunorrubicina/farmacologia , Daunorrubicina/uso terapêutico , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adulto Jovem
5.
Biomed Pharmacother ; 119: 109399, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31521893

RESUMO

Acute lymphoblastic leukemia (ALL), usually treated with chemotherapy, has limited therapeutic effects and high toxicity. Upregulation of HSP70 induces tumor development, however, the molecular mechanism of HSP70 in ALL remains unclear. In our research, we aimed to investigate the role of HSP70 in ALL, specifically the molecular mechanisms underlying cell apoptosis and proliferation. We found that HSP70 expression in leukomonocytes from ALL patients was increased compared with the control group. HSP70 expression in NALM-6 and BE-13 was also up-regulated contrast with AHH-1. Inhibition of HSP70 significantly promoted cell apoptosis and suppressed cell proliferation in ALL cell lines. Suppression of HSP70 decreased TAK1 and increased Egr-1 protein expression. Further experiments indicated that overexpression of TAK1 ameliorated the effect of HSP70 inhibition on Egr-1 protein expression, cell apoptosis and proliferation. In order to determine whether the effect of HSP70 inhibition on apoptosis and proliferation of ALL cell lines could be achieved via regulation of Egr-1, we performed a loss-of-function experiment for Egr-1. Egr-1 suppression was found to reverse the effect of HSP70 inhibition on cell apoptosis and proliferation in ALL. Taken together, our results suggest that HSP70 inhibition upregulates Egr-1 via TAK1, inducing apoptosis and restricting proliferation in ALL cells.


Assuntos
Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adolescente , Adulto , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Criança , Pré-Escolar , Regulação Leucêmica da Expressão Gênica , Humanos , Lactente , Recém-Nascido , Monócitos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adulto Jovem
6.
Blood ; 134(15): 1257-1268, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31395602

RESUMO

Relapse remains the main cause of MLL-rearranged (MLL-r) acute lymphoblastic leukemia (ALL) treatment failure resulting from persistence of drug-resistant clones after conventional chemotherapy treatment or targeted therapy. Thus, defining mechanisms underlying MLL-r ALL maintenance is critical for developing effective therapy. PRMT1, which deposits an asymmetric dimethylarginine mark on histone/non-histone proteins, is reportedly overexpressed in various cancers. Here, we demonstrate elevated PRMT1 levels in MLL-r ALL cells and show that inhibition of PRMT1 significantly suppresses leukemic cell growth and survival. Mechanistically, we reveal that PRMT1 methylates Fms-like receptor tyrosine kinase 3 (FLT3) at arginine (R) residues 972 and 973 (R972/973), and its oncogenic function in MLL-r ALL cells is FLT3 methylation dependent. Both biochemistry and computational analysis demonstrate that R972/973 methylation could facilitate recruitment of adaptor proteins to FLT3 in a phospho-tyrosine (Y) residue 969 (Y969) dependent or independent manner. Cells expressing R972/973 methylation-deficient FLT3 exhibited more robust apoptosis and growth inhibition than did Y969 phosphorylation-deficient FLT3-transduced cells. We also show that the capacity of the type I PRMT inhibitor MS023 to inhibit leukemia cell viability parallels baseline FLT3 R972/973 methylation levels. Finally, combining FLT3 tyrosine kinase inhibitor PKC412 with MS023 treatment enhanced elimination of MLL-r ALL cells relative to PKC412 treatment alone in patient-derived mouse xenografts. These results indicate that abolishing FLT3 arginine methylation through PRMT1 inhibition represents a promising strategy to target MLL-r ALL cells.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/metabolismo , Tirosina Quinase 3 Semelhante a fms/metabolismo , Animais , Apoptose , Proliferação de Células , Sobrevivência Celular , Rearranjo Gênico , Humanos , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Células Tumorais Cultivadas
8.
Oncol Rep ; 42(5): 2016-2028, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31436300

RESUMO

The restricted expression of Wilms tumor 1 (WT1) and cyclin A1 (CCNA1) in normal tissues, as opposed to their abnormal expression in leukemia demonstrates the applicability of WT1 and CCNA1 as cancer antigens for immunotherapy, and as markers for prognosis and relapse. In this study, the WT1 and CCNA1 mRNA levels were found to be elevated in bone marrow samples from pediatric acute promyelocytic leukemia (APL or AML­M3) patients, and to be quite varied in pediatric acute lymphocytic leukemia (ALL) patients, compared to non­leukemic bone marrow controls. Consistent with the observed upregulation of both WT1 and CCNA1 in APL, WT1 overexpression elevated the CCNA1 mRNA levels in K562 leukemia cells. Treatment with curcumin decreased the WT1 levels in K562 cells, and also decreased CCNA1 protein expression. The examination of the CCNA1 promoter identified potential canonical WT1 binding sites within the 3­kb region upstream of the transcription start site. Chromatin immunoprecipitation and luciferase reporter assays confirmed WT1 binding and the activation of the CCNA1 promoter. Furthermore, the GC­rich core CCNA1 promoter region provided additional non­canonical WT1 activation sites, as revealed by promoter assays. The importance of the GC­rich core region of the CCNA1 promoter was confirmed by treating the K562 cells with mithramycin A, which blocks the binding of zinc finger transcription factors to GC­rich sequences. Mithramycin A subsequently suppressed both CCNA1 promoter activity and protein expression in the K562 cells. Taken together, the data from the WT1 overexpression, and curcumin and mithramycin A treatment experiments, as well as those from chromatin binding assays, along with inferences from patient RNA analyses, establish a plausible link between WT1 and CCNA1, and support the functional significance of an elevated WT1 expression in leukemia, which may also affect CCNA1 expression.


Assuntos
Ciclina A1/genética , Leucemia Promielocítica Aguda/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas WT1/genética , Adolescente , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Criança , Pré-Escolar , Curcumina/farmacologia , Ciclina A1/química , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lactente , Células K562 , Leucemia Promielocítica Aguda/metabolismo , Masculino , Plicamicina/análogos & derivados , Plicamicina/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Proteínas WT1/química , Proteínas WT1/metabolismo
9.
Med Sci (Paris) ; 35(6-7): 497-500, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31274074

Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Hematológicas/terapia , Imunoterapia Adotiva/métodos , Proteína Acessória do Receptor de Interleucina-1/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Animais , Anticorpos Monoclonais/genética , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Caspase 9/genética , Proteínas de Fusão bcr-abl/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes Transgênicos Suicidas , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunoterapia Adotiva/efeitos adversos , Proteína Acessória do Receptor de Interleucina-1/genética , Proteína Acessória do Receptor de Interleucina-1/imunologia , Células Matadoras Naturais/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/transplante , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/imunologia
10.
Pediatr Hematol Oncol ; 36(4): 222-235, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31313940

RESUMO

We investigated bone marrow (BM) recovery of hematopoietic stem cells (HSC) and hematopoietic microenvironment after chemotherapy in childhood acute lymphoblastic leukemia (ALL). Twenty-nine de novo childhood ALL patients were enrolled and BM biopsy sections at diagnosis (BM0), after induction (BM1), consolidation (BM3), interim maintenance (BM5) and delayed intensification (BM7) chemotherapy were obtained. Expressions of CD133, CD34, CD117, osteopontin, osteonectin, CXCL12, and CXCR4 were evaluated by semiquantitative immunohistochemical stains. All markers recovered significantly following chemotherapy while highest values at BM3 (for CD133/CD117/CXCL12/CXCR4), BM5 (for CXCL12/CD34/osteonectin), and BM7 (for osteopontin). Patients with cytogenetic good risk expressed significantly more CD133+/CD34+ cells than those with standard and poor risk in BM5. Patients without aberrant immunophenotype expressed significantly more CD133+ cells in BM1, and more CD117+ cells in BM5 than those with aberrant immunophenotype. Patients treated with standard risk-average chemotherapeutic protocol expressed significantly more CXCR4+ cells than those treated with other protocols in BM7. Patients who showed lowest ANC ≥ 200/µL during induction chemotherapy expressed significantly more CXCR4+ cells at from BM1 to BM5, and more CD133+ cells in BM3 than those who did not. Early and full recovery of BM HSC is most vigorous at BM3 and BM5, respectively. Reconstruction of BM niche and stromal cell recovery is mostly active at BM5, and hematopoietic activity of BM niche recovers mostly at BM7. Patients with cytogenetic good risk, nonaberrant immunophenotype, standard risk-average chemotherapeutic protocol and less BM suppression during induction chemotherapy show prompt recovery of some BM HSC and microenvironment markers compared to others.


Assuntos
Medula Óssea/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras , Recuperação de Função Fisiológica , Adolescente , Medula Óssea/patologia , Criança , Pré-Escolar , Feminino , Seguimentos , Células-Tronco Hematopoéticas/patologia , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Células Estromais/metabolismo , Células Estromais/patologia
11.
Genes Chromosomes Cancer ; 58(11): 815-819, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31340073

RESUMO

Minimal residual disease (MRD) assessment is an essential tool in contemporary acute lymphoblastic leukemia (ALL) protocols, being used for therapeutic decisions such as hematopoietic stem cell transplantation in high-risk patients. However, a significant proportion of adult ALL patients with negative MRD still relapse suggesting that other factors (ie, molecular alterations) must be considered in order to identify those patients with high risk of disease progression. We have identified partial IKZF1 gene deletions and CDKN2A/B deletions as markers of disease recurrence and poor survival in a series of uniformly treated adolescent and adult Philadelphia chromosome-negative B-cell progenitor ALL patients treated according to the Programa Español de Tratamientos en Hematología protocols. Importantly, CDKN2A/B deletions showed independent significance of MRD at the end of induction, which points out the need for treatment intensification in these patients despite being MRD-negative after induction therapy.


Assuntos
Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adolescente , Adulto , Biomarcadores Tumorais , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Progressão da Doença , Feminino , Deleção de Genes , Humanos , Fator de Transcrição Ikaros/metabolismo , Masculino , Neoplasia Residual , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Prognóstico , Recidiva
12.
Med Sci Monit ; 25: 5211-5218, 2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31301225

RESUMO

BACKGROUND T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy caused by abnormal proliferation of immature T cell progenitors. Chemotherapy of T-ALL usually consists of induction, consolidation, and long-term maintenance. Diacetyl hexamethylene diamine (CAHB) is a newly developed agent that induces the differentiation of malignant cells and deprives their clonal growth ability. Since its effect on T-ALL has not been previously determined, we evaluated its potential function in the Jurkat cell line. MATERIAL AND METHODS MTT assay was conducted to evaluate the cytotoxicity and anti-proliferative effect of CAHB. The apoptosis level of CAHB-treated Jurkat cells was evaluated using flow cytometry via staining with Annexin V/PI or cleaved-caspase-3. The alteration of mitochondrial membrane potential was determined by flow cytometry. The expression of Bax and Bcl-2 was evaluated by RT-PCR and Western blot. Western blot was also used to assess the activation of Akt. RESULTS CAHB inhibited the proliferation and promoted the apoptosis of Jurkat cells in a time- and dose-dependent manner by decreasing activation of Akt, reducing the mitochondrial membrane potential, and downregulating the Bcl-2/Bax ratio. CONCLUSIONS Our data suggest that CAHB might be regarded as a novel treatment agent for T-ALL since it can induce apoptosis and inhibit proliferation of the T-ALL cell line at a relatively low level.


Assuntos
Diaminas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diacetil , Diaminas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Células Jurkat , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Cells ; 8(7)2019 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-31337120

RESUMO

Dendritic cells and macrophages are common components of the tumour immune microenvironment and can contribute to immune suppression in both solid and haematological cancers. The Bone Morphogenetic Protein (BMP) pathway has been reported to be involved in cancer, and more recently in leukaemia development and progression. In the present study, we analyse whether acute lymphoblastic leukaemia (ALL) cells can affect the differentiation of dendritic cells and macrophages and the involvement of BMP pathway in the process. We show that ALL cells produce BMP4 and that conditioned media from ALL cells promote the generation of dendritic cells with immunosuppressive features and skew M1-like macrophage polarization towards a less pro-inflammatory phenotype. Likewise, BMP4 overexpression in ALL cells potentiates their ability to induce immunosuppressive dendritic cells and favours the generation of M2-like macrophages with pro-tumoral features. These results suggest that BMP4 is in part responsible for the alterations in dendritic cell and macrophage differentiation produced by ALL cells.


Assuntos
Proteína Morfogenética Óssea 4/fisiologia , Células Dendríticas/patologia , Macrófagos/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Microambiente Tumoral , Diferenciação Celular , Linhagem Celular Tumoral , Humanos , Ativação de Macrófagos
14.
Clin Nucl Med ; 44(9): e529-e531, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31306192

RESUMO

PSMA PET/CT is known to show uptake in various benign and malignant processes. The following PSMA PET/CT was performed for prostate carcinoma staging (Gleason 3 + 4 left apex; PSA 5.8). It shows incidental diffuse PSMA marrow uptake, not typical for prostate metastatic disease. No treatment had been commenced at the time of the scan. Serology and bone marrow biopsy showed B-cell acute lymphocytic leukemia. Focal PSMA uptake in the right ischium was correlated with a T1 hypointense lesion on a previous MRI and was convincing for a skeletal metastasis. Alternative diagnoses in diffuse skeletal PSMA uptake need therefore to be considered.


Assuntos
Glutamato Carboxipeptidase II/metabolismo , Achados Incidentais , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico por imagem , Idoso , Humanos , Masculino , Estadiamento de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia
15.
J Exp Clin Cancer Res ; 38(1): 269, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221196

RESUMO

BACKGROUND: Drug-resistant cell lines, established from drug-sensitive cell lines by drug exposure in vitro, are the most useful cancer models in studies on the mechanism of chemoresistance. However, the success rate of the traditional approaches to construct such cell lines is low because a long time is required for the addition of drugs. METHODS: A cell culture technique was used to establish the drug-resistant cell lines from their parental cells. Molecular and cellular biological techniques including flow cytometry, MTT assay, western blotting, and DNA fingerprinting analysis were used to characterize the drug-resistant cell lines. Nude mice were used for xenograft studies. RESULTS: We established novel glucocorticoid (GC)-resistant cell lines from 3 GC-sensitive acute lymphoblastic leukemia (ALL) cell lines. First, we established a novel GC-resistant T-ALL cell line, CEM-C7/HDR, by mimicking the microenvironment of the bone marrow and culturing GC-sensitive CEM-C7-14 cells under hypoxia for 5 weeks with a single dexamethasone (Dex) treatment. The CEM-C7/HDR cells had been cultured continuously in drug-free medium under normoxia for 1 year. The IC50 and resistance index (RI) to Dex were maintained at 60~70 µM and 1500~1800, respectively, which is in consistent with the IC50 and RI of GC-resistant CEM-C1-15 cells. To clarify the reliability of the method, we subcloned CEM-C7-14 cells, and obtained Dex-resistant cell lines, CEM-C7-SC2/HDR and CEM-C7-SC14/HDR, from 2 monoclonal cells of CEM-C7-14 by the same method. Moreover, we obtained two additional Dex-resistant B-ALL cell lines, NALM-6/HDR and HXEX-ALL1/HDR, from NALM-6 and HXEX-ALL1 cells with the same approach. CONCLUSIONS: CEM-C7/HDR, NALM-6/HDR and HXEX-ALL1/HDR cell lines may serve as useful GC-resistant ALL models for both in vitro and in vivo studies. Culturing under hypoxic condition with a single Dex treatment is a novel and convenient approach for generating stable GC resistant cell lines.


Assuntos
Técnicas de Cultura de Células/métodos , Dexametasona/farmacologia , Resistencia a Medicamentos Antineoplásicos , Glucocorticoides/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Animais , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo
16.
Eur J Haematol ; 103(3): 215-224, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31206203

RESUMO

AIM: This study aimed to investigate the possible functions of interaction between JARID1B and miR-137 in ALL. METHODS: The levels of H3K4me3 and H3K4me2 and the expression of JARID1B and miR-137 were analyzed in six ALL cell lines and 30 ALL patients. The effects of miR-137 and JARID1B on cell proliferation and apoptosis were investigated by silencing or promoting the respective genes. The interaction between miR-137 and JARID1B was confirmed by double-luciferase report assay. RESULTS: The histone H3K4 expressions and miR-137 expression were lower in 30 ALL patients and in six ALL cell lines, while the expression of JARID1B was elevated. A negative correlation was observed between JARID1B and miR-137. Over-expression of miR-137 led to decreasing cell proliferation and increasing apoptosis in MOLT-4 and BALL-1 cells. MiR-137 inhibitor up-regulated JARID1B in these two cell lines, while promoted proliferation in BALL-1 cells only. Dual-luciferase report assay suggested that JARID1B was a direct target of miR-137 in ALL cell lines. CONCLUSIONS: The expression of miR-137 was declined in ALL, and JARID1B was directly repressed by miR-137. Aberrant JARID1B expression could result in abnormal histone methylation, which might be one cause of ALL.


Assuntos
Regulação Leucêmica da Expressão Gênica , Histona Desmetilases com o Domínio Jumonji/genética , MicroRNAs/genética , Proteínas Nucleares/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Interferência de RNA , Proteínas Repressoras/genética , Regiões 3' não Traduzidas , Adolescente , Adulto , Idoso , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Genes Reporter , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Repressoras/metabolismo , Adulto Jovem
17.
Bioelectromagnetics ; 40(5): 343-353, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31157932

RESUMO

Exposure to extremely low-frequency magnetic fields (ELF-MFs) has been classified by the International Agency for Research on Cancer (IARC) as "possibly carcinogenic to humans," based on limited scientific evidence concerning childhood leukemia. This assessment emphasized the lack of appropriate animal models recapitulating the natural history of this disease. Childhood B-cell acute lymphoblastic leukemia (B-ALL) is the result of complex interactions between genetic susceptibility and exposure to exogenous agents. The most common chromosomal alteration is the ETV6-RUNX1 fusion gene, which confers a low risk of developing the malignancy by originating a preleukemic clone requiring secondary hits for full-blown disease to appear. To develop potential prophylactic interventions, we need to identify the environmental triggers of the second hit. Recently, we generated a B-ALL mouse model of the human ETV6-RUNX1+ preleukemic state. Here, we present the results from the ARIMMORA pilot study, obtained by exposing 34 Sca1-ETV6-RUNX1 mice (vs. 27 unexposed) to a 50 Hz magnetic field of 1.5 mT with both fundamental and harmonic content, with an on/off cycle of 10 min/5 min, for 20 h/day, from conception until 3 months of age. Mice were monitored until 2 years of age and peripheral blood was periodically analyzed by flow cytometry. One of the exposed mice developed B-ALL while none of the non-exposed did. Although the results are statistically non-significant due to the limited number of mice used in this pilot experiment, overall, the results show that the newly developed Sca1-ETV6-RUNX1 mouse can be successfully used for ELF-MF exposure studies about the etiology of childhood B-ALL. Bioelectromagnetics. 2019;40:343-353. © 2019 Bioelectromagnetics Society.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Modelos Animais de Doenças , Campos Eletromagnéticos/efeitos adversos , Leucemia Experimental , Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteínas Proto-Oncogênicas c-ets/genética , Ondas de Rádio/efeitos adversos , Proteínas Repressoras/genética , Animais , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Feminino , Humanos , Leucemia Experimental/genética , Leucemia Experimental/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Projetos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogênicas c-ets/metabolismo , Proteínas Repressoras/metabolismo
18.
Cancer Genet ; 233-234: 7-20, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31109597

RESUMO

An alarming increase in acute lymphoblastic leukemia among children and males has drawn attention of investigators to delve into the genetic causes of ALL and to discover new therapeutic strategies with better prognosis. Although the survival rate in children is much higher than adults, but there's a need to find new potential molecular targets with better treatment outcome. Genomic profiling has made it possible to identify various genetic defects important for driving leukemogenesis. Study of the genetic lesions not only give a better understanding of genes function but also helps to target various signaling pathways involved in disease progression. The current review provides an overview of important genetic defects and dysregulation in their downstream signaling pathways in acute lymphoblastic leukemia.


Assuntos
Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Transdução de Sinais , Progressão da Doença , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo
19.
Biomed Pharmacother ; 115: 108913, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31054507

RESUMO

Suppressor of cytokine signaling 3 (SOCS3) has been characterized as one of the most crucial negative regulator in the JAK2/STAT3 signaling pathway. However, there are few studies on the relationship between SOCS3 and pediatric acute lymphoblastic leukemia (ALL). This study analyzes the influence of SOCS3 expression on the risk and the progression of pediatric ALL and the underlying mechanism. The levels of SOCS3, p-JAK2, p-STAT3, SOCS3 methylation, CD4+CD25+CD127lowTreg were detected by PCR, laser confocal microscopy, western blot, bisulfite sequencing and flow cytometry at different progression of ALL. We found that the SOCS3 expression level at initial diagnosis (DG) of ALL patients was significantly lower than that of healthy controls (HC), while the expression of SOCS3 methylation was opposite. The expression of SOCS3 and SOCS3 methylation were returned to normal in the complete remission (CR) stage, and there were no difference between resistance, relapse and initial diagnosis. The expression of SOCS3 decreased and weakened the inhibition of pSTAT3 expression in DG, resistance and relapse groups. The levels of Treg cells in ALL children were significantly higher than those in the HC children. There was a positive correlation between the expression level of STAT3 and the expression level of Treg cells in children with ALL, while that was negatively correlated with the expression levels of Treg cells. Compared with high-level of SOCS3, the low-level of SOCS3 patients had more high risk factors, as higher WBC counts, LDH level and much more poor prognostic genes. SOCS3 methylation leads to low-expression of SOCS3, which can lead to continuous activation of JAK/STAT3 and increased expression of Treg cells, which in turn affects the anti-tumor immunological effect of the body. Taken together, our data show that monitoring the level of SOCS3 can contribute to the understanding of the state of illness and evaluate the risk of progression of ALL.


Assuntos
Janus Quinase 2/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Regiões Promotoras Genéticas , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética , Estudos de Casos e Controles , Criança , Metilação de DNA , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transdução de Sinais , Linfócitos T Reguladores/metabolismo , Resultado do Tratamento
20.
Int J Lab Hematol ; 41 Suppl 1: 126-130, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31069976

RESUMO

BCR-ABL1-like B-lymphoblastic leukemia/lymphoma (BCR-ABL1-like ALL or Ph-like ALL) is a neoplastic proliferation of lymphoblasts that has a gene expression profile similar to that of B-ALL with t(9;22)(q34.1;q11.2) BCR-ABL1, but lacks that gene fusion. It is associated with poor prognosis and is seen in 10%-20% of pediatric cases and 20%-30% of adult cases of ALL. It is included as a provisional entity in the revised 4th edition of the WHO Classification. A variety of different genetic abnormalities are identified in this entity, but they all converge on pathways that are potentially responsive to the addition of targeted therapy to conventional chemotherapy. Thus, it is important to screen for BCR-ABL1-like ALL, particularly in adults and pediatric patients with high-risk clinical features. Here, we provide a brief overview of the genetic profile and clinical features of BCR-ABL1-like ALL and review laboratory methodologies for routine identification of this genetically heterogeneous entity.


Assuntos
Proteínas de Fusão bcr-abl , Perfilação da Expressão Gênica/métodos , Regulação Leucêmica da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Adulto , Criança , Feminino , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA