Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 10.618
Filtrar
1.
Nutrients ; 13(8)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34444931

RESUMO

Over the centuries, humans have traditionally used garlic (Allium sativum L.) as a food ingredient (spice) and remedy for many diseases. To confirm this, many extensive studies recognized the therapeutic effects of garlic bulbs. More recently, black garlic (BG), made by heat-ageing white garlic bulbs, has increased its popularity in cuisine and traditional medicine around the world, but there is still limited information on its composition and potential beneficial effects. In this study, the metabolite profile of methanol extract of BG (BGE) was determined by high-performance liquid chromatography coupled to tandem mass spectrometry in high-resolution mode. Results allowed to establish that BGE major components were sulfur derivatives, saccharides, peptides, organic acids, a phenylpropanoid derivative, saponins, and compounds typical of glycerophospholipid metabolism. Characterization of the BGE action in cancer cells revealed that antioxidant, metabolic, and hepatoprotective effects occur upon treatment as well as induction of maturation of acute myeloid leukemia cells. These results are interesting from the impact point of view of BG consumption as a functional food for potential prevention of metabolic and tumor diseases.


Assuntos
Alho/química , Leucemia Mieloide Aguda/tratamento farmacológico , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Antioxidantes/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Leucemia Mieloide Aguda/patologia , Peptídeos/análise , Raízes de Plantas/química , Polissacarídeos/análise , Saponinas/análise , Especiarias/análise , Enxofre/análise , Espectrometria de Massas em Tandem/métodos , Células U937
2.
Hematology ; 26(1): 565-576, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34384344

RESUMO

Objectives: Multipotent mesenchymal stromal cells (MSC) play a pivotal role in the bone marrow (BM) niche. Stanniocalcin 1 (STC1) secreted by MSC has been demonstrated to promote the survival of neoplastic cells and was suggested a marker for minimal residual disease of acute myeloid leukemia (AML). Therefore, we evaluated the expression of STC1 in MSC from AML patients (MSCAML) compared to MSC from healthy donors (MSCHD).Methods: Liquid culture assays of MSCAML and MSCHD were performed to compare expansion capacity. Gene expression profiles of MSCAML vs. MSCHD were established. Secretion of STC1 was tested by ELISA in MSCAML vs. MSCHD and expression of STC1 in AML- vs. HD-BM by immunohistochemistry. In addition, co-cultures of AML cells on MSC were initiated and ultrastructural intercellular communication patterns were investigated. Finally, the effect of blocking STC1 on AML cells was evaluated.Results: MSCAML showed significant decreased expansion capacity compared to MSCHD. Gene analysis revealed marked overexpression of STC1 in MSCAML. ELISA and immunohistochemical findings confirmed this observation. Electron microscopy analysis showed reciprocal stimulation between AML cells and MSC. Blockade of STC1 did not significantly affect AML cell proliferation and apoptosis.Discussion: Characteristics of MSC differ depending on whether they originate from AML patients or from HD. STC1 was mostly overexpressed in MSCAML compared to MSCHD. In vitro blockade of STC1, however, was not associated with AML cell proliferation and apoptosis.Conclusion: Differences in expression levels of glycoproteins from MSCAML compared to MSCHD not necessarily assume that these molecules are niche-relevant in leukemic disease.


Assuntos
Glicoproteínas/genética , Leucemia Mieloide Aguda/genética , Células-Tronco Mesenquimais/patologia , Regulação para Cima , Adulto , Idoso , Células Cultivadas , Feminino , Glicoproteínas/análise , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Células Tumorais Cultivadas
3.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202238

RESUMO

Acute myeloid leukemia (AML) is a hematologic malignancy caused by a wide range of alterations responsible for a high grade of heterogeneity among patients. Several studies have demonstrated that the hypoxic bone marrow microenvironment (BMM) plays a crucial role in AML pathogenesis and therapy response. This review article summarizes the current literature regarding the effects of the dynamic crosstalk between leukemic stem cells (LSCs) and hypoxic BMM. The interaction between LSCs and hypoxic BMM regulates fundamental cell fate decisions, including survival, self-renewal, and proliferation capacity as a consequence of genetic, transcriptional, and metabolic adaptation of LSCs mediated by hypoxia-inducible factors (HIFs). HIF-1α and some of their targets have been associated with poor prognosis in AML. It has been demonstrated that the hypoxic BMM creates a protective niche that mediates resistance to therapy. Therefore, we also highlight how hypoxia hallmarks might be targeted in the future to hit the leukemic population to improve AML patient outcomes.


Assuntos
Medula Óssea/metabolismo , Medula Óssea/patologia , Hipóxia/metabolismo , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/metabolismo , Microambiente Tumoral , Animais , Linhagem Celular Tumoral , Reprogramação Celular , Gerenciamento Clínico , Suscetibilidade a Doenças , Metabolismo Energético , Epigênese Genética , Regulação Leucêmica da Expressão Gênica , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Terapia de Alvo Molecular , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais
4.
Lancet Haematol ; 8(8): e552-e561, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34329576

RESUMO

BACKGROUND: Addition of the BCL2 inhibitor venetoclax to lower intensity therapy has been shown to improve overall survival in older (aged 75 years or older) and unfit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to investigate the activity of venetoclax combined with intensive chemotherapy in patients aged 65 years or younger with acute myeloid leukaemia. METHODS: This cohort study was done at the MD Anderson Cancer Center in the USA, as part of the single-centre, single arm, phase 2, CLIA trial. Here we report on the independent cohort investigating the safety and activity of venetoclax added to intensive chemotherapy (the CLIA regimen [cladribine, high-dose cytarabine, idarubicin]). Eligible patients were aged 18-65 years with a new diagnosis of acute myeloid leukaemia, mixed phenotype acute leukaemia, or high-risk myelodysplastic syndrome (≥10% blasts or International Prognostic Scoring System ≥2 [intermediate]), who received no previous potentially curative therapy for leukaemia. Patients received cladribine (5 mg/m2) and cytarabine (1·5 g/m2 for patients aged <60 years, 1 g/m2 for patients aged ≥60 years) intravenously on days 1-5 and idarubicin (10 mg/m2) intravenously on days 1-3. Consolidation was cladribine (5 mg/m2) and cytarabine (1 g/m2 for patients aged <60 years and 0·75 g/m2 for patients aged ≥60 years) on days 1-3 and idarubicin (8 mg/m2) on days 1-2. Venetoclax (400 mg) was given on days 2-8 with each course. Patients with a known FLT3-ITD or FLT3-TKD mutation received midostaurin or gilteritinib. The primary outcome was composite complete response (complete response plus complete response with incomplete blood count recovery). Secondary outcomes were overall response, duration of response, event-free survival, overall survival, and safety. This trial was registered with ClinicalTrials.gov, NCT02115295. FINDINGS: Between Feb 25, 2019, and March 23, 2021, 77 patients were assessed for eligibility, 50 of whom were enrolled. Median age was 48 years (IQR 37-56). 47 (94% [95% CI 83-98]) patients had composite complete response, with the same proportion also having an overall response; two (4% [1-14]) patients did not respond, and one (2% [0-11]) patient died during induction. 37 (82% [95% CI 68-92]) of 45 patients had undetectable measurable residual disease (MRD). At a median follow-up of 13·5 months (IQR 6·4-19·5), the median duration of response, event-free survival, and overall survival were not reached. At 12 months, the estimated duration of response was 74% (95% CI 60-92), event-free survival was 68% (54-85), and overall survival was 85% (75-97). The most common adverse events of grade 3 or worse were febrile neutropenia (42 [84%] patients), infection (six [12%]), and alanine aminotransferase elevations (six [12%]). There was one death during induction in a patient treated with CLIA-venetoclax plus a FLT3 inhibitor. Two patients died of infectious complications while in complete response in consolidation cycles, both of whom had FLT3-mutated acute myeloid leukaemia and were receiving combined therapy with a FLT3 inhibitor. No deaths were deemed to be treatment related. INTERPRETATION: Venetoclax added to CLIA was safe and active in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, producing high rates of durable MRD-negative remissions and encouraging event-free survival and overall survival. FUNDING: MD Anderson Cancer Center.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Adolescente , Adulto , Idoso , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Cladribina/administração & dosagem , Estudos de Coortes , Citarabina/administração & dosagem , Feminino , Seguimentos , Humanos , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Prognóstico , Indução de Remissão , Fatores de Risco , Sulfonamidas/administração & dosagem , Adulto Jovem
5.
Commun Biol ; 4(1): 868, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262131

RESUMO

Hematopoietic stem/progenitor cell (HSPC) and leukemic cell homing is an important biological phenomenon that occurs through key interactions between adhesion molecules. Tethering and rolling of the cells on endothelium, the crucial initial step of the adhesion cascade, is mediated by interactions between selectins expressed on endothelium to their ligands expressed on HSPCs/leukemic cells in flow. Although multiple factors that affect the rolling behavior of the cells have been identified, molecular mechanisms that enable the essential slow and stable cell rolling remain elusive. Here, using a microfluidics-based single-molecule live cell fluorescence imaging, we reveal that unique spatiotemporal dynamics of selectin ligands on the membrane tethers and slings, which are distinct from that on the cell body, play an essential role in the rolling of the cell. Our results suggest that the spatial confinement of the selectin ligands to the tethers and slings together with the rapid scanning of a large area by the selectin ligands, increases the efficiency of selectin-ligand interactions during cell rolling, resulting in slow and stable rolling of the cell on the selectins. Our findings provide novel insights and contribute significantly to the molecular-level understanding of the initial and essential step of the homing process.


Assuntos
Selectina E/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Microfluídica/métodos , Imagem Individual de Molécula/métodos , Algoritmos , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Células Cultivadas , Células-Tronco Hematopoéticas/citologia , Humanos , Leucemia Mieloide Aguda/patologia , Ligantes , Microscopia Eletrônica de Varredura , Microscopia de Fluorescência/métodos , Modelos Biológicos
6.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298882

RESUMO

Platelets can modulate cancer through budding of platelet microparticles (PMPs) that can transfer a plethora of bioactive molecules to cancer cells upon internalization. In acute myelogenous leukemia (AML) this can induce chemoresistance, partially through a decrease in cell activity. Here we investigated if the internalization of PMPs protected the monocytic AML cell line, THP-1, from apoptosis by decreasing the initial cellular damage inflicted by treatment with daunorubicin, or via direct modulation of the apoptotic response. We examined whether PMPs could protect against apoptosis after treatment with a selection of inducers, primarily associated with either the intrinsic or the extrinsic apoptotic pathway, and protection was restricted to the agents targeting intrinsic apoptosis. Furthermore, levels of daunorubicin-induced DNA damage, assessed by measuring gH2AX, were reduced in both 2N and 4N cells after PMP co-incubation. Measuring different BCL2-family proteins before and after treatment with daunorubicin revealed that PMPs downregulated the pro-apoptotic PUMA protein. Thus, our findings indicated that PMPs may protect AML cells against apoptosis by reducing DNA damage both dependent and independent of cell cycle phase, and via direct modulation of the intrinsic apoptotic pathway by downregulating PUMA. These findings further support the clinical relevance of platelets and PMPs in AML.


Assuntos
Apoptose/fisiologia , Micropartículas Derivadas de Células/fisiologia , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/fisiologia , Daunorrubicina/farmacologia , Células THP-1/fisiologia , Apoptose/efeitos dos fármacos , Plaquetas , Micropartículas Derivadas de Células/efeitos dos fármacos , Micropartículas Derivadas de Células/metabolismo , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Células THP-1/efeitos dos fármacos , Células THP-1/metabolismo
7.
Cancer Sci ; 112(9): 3419-3426, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34159709

RESUMO

Acute myeloid leukemia (AML) is hierarchically organized by self-renewing leukemic stem cells (LSCs). LSCs originate from hematopoietic stem cells (HSCs) by acquiring multistep leukemogenic events. To specifically eradicate LSCs, while keeping normal HSCs intact, the discrimination of LSCs from HSCs is important. We have identified T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) as an LSC-specific surface molecule in human myeloid malignancies and demonstrated its essential function in maintaining the self-renewal ability of LSCs. TIM-3 has been intensively investigated as a "coinhibitory" or "immune checkpoint" molecule of T cells. However, little is known about its distinct function in T cells and myeloid malignancies. In this review, we discuss the structure of TIM-3 and its function in normal blood cells and LSCs, emphasizing the specific signaling pathways involved, as well as the therapeutic applications of TIM-3 molecules in human myeloid malignancies.


Assuntos
Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/química , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais , Animais , Humanos , Leucemia Mieloide Aguda/patologia , Estrutura Molecular , Linfócitos T/metabolismo
8.
Commun Biol ; 4(1): 799, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172833

RESUMO

The presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD + AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD + AML.


Assuntos
Citoesqueleto de Actina/fisiologia , Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Estaurosporina/análogos & derivados , Tirosina Quinase 3 Semelhante a fms/genética , Citoesqueleto de Actina/química , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Pironas/farmacologia , Quinolinas/farmacologia , Estaurosporina/farmacologia , Sulfonamidas/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/fisiologia , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Proteínas rac1 de Ligação ao GTP/fisiologia
9.
Methods Mol Biol ; 2348: 167-174, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34160806

RESUMO

Developing strategies to target lncRNAs are needed. In this chapter, we describe in detail a method to deliver antisense oligonucleotides into acute myeloid leukemia cells using lipid nanoparticles tagged with the transferrin receptor. While this chapter is focused on the delivery method, we also discuss important considerations about the design of antisense oligonucleotides (ASOs). The strategy described here has been used successfully to deliver ASOs into leukemic blasts and stem cells.


Assuntos
Portadores de Fármacos , Leucemia Mieloide Aguda/genética , Lipídeos , Nanopartículas , Nucleotídeos/administração & dosagem , Interferência de RNA , RNA Longo não Codificante/genética , Ribose/análogos & derivados , Linhagem Celular Tumoral , Portadores de Fármacos/química , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Lipídeos/química , Lipossomos , Nanopartículas/química , Tamanho da Partícula , Polietilenoglicóis , Ribose/administração & dosagem
10.
J Ayub Med Coll Abbottabad ; 33(2): 335-338, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34137556

RESUMO

Bone-marrow being a home to various kinds of normal hematopoietic cells, sometime becomes overcrowded by abnormal cell population in malignancies like in acute myeloid leukaemia. One such dilemma in diagnosis betides when two abnormal cell populations in bone-marrow occur at the same time. A prime example is when reactive plasmacytosis in bone-marrow eventuate in relation with acute myeloid leukaemia (AML). Due to scarce amount of such cases reported, it is imperative to understand the difference between reactive plasmacytosis which arises after induction of chemotherapy and the one which is diagnosed along with AML, during initial diagnosis due to other causes, like infections and IL-6 production by the leukemic blast population. To substantiate these erstwhile arguments, the brief case history of a 45 years old female patient diagnosed with acute myeloid leukaemia with coincident reactive plasmacytosis having no previous history of chemotherapy is presented along with review of past published literature.


Assuntos
Medula Óssea/patologia , Leucemia Mieloide Aguda/diagnóstico , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Pessoa de Meia-Idade
11.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068078

RESUMO

Anthracyclines remain a cornerstone of induction chemotherapy for acute myeloid leukemia (AML). Refractory or relapsed disease due to chemotherapy resistance is a major obstacle in AML management. MicroRNAs (miRNAs) have been observed to be involved in chemoresistance. We previously observed that miR-15a-5p was overexpressed in a subgroup of chemoresistant cytogenetically normal AML patients compared with chemosensitive patients treated with daunorubicin and cytarabine. MiR-15a-5p overexpression in AML cells reduced apoptosis induced by both drugs in vitro. This study aimed to elucidate the mechanisms by which miR-15a-5p contributes to daunorubicin resistance. We showed that daunorubicin induced autophagy in myeloid cell lines. The inhibition of autophagy reduced cell sensitivity to daunorubicin. The overexpression of miR-15a-5p decreased daunorubicin-induced autophagy. Conversely, the downregulation of miR-15a-5p increased daunorubicin-induced autophagy. We found that miR-15a-5p targeted four genes involved in autophagy, namely ATG9a, ATG14, GABARAPL1 and SMPD1. Daunorubicin increased the expression of these four genes, and miR-15a-5p counteracted this regulation. Inhibition experiments with the four target genes showed the functional effect of miR-15a-5p on autophagy. In summary, our results indicated that miR-15a-5p induces chemoresistance in AML cells through the abrogation of daunorubicin-induced autophagy, suggesting that miR-15a-5p could be a promising therapeutic target for chemoresistant AML patients.


Assuntos
Biomarcadores Tumorais/metabolismo , Daunorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Leucemia Mieloide Aguda/tratamento farmacológico , MicroRNAs/genética , Adulto , Antibióticos Antineoplásicos/farmacologia , Apoptose , Autofagia , Biomarcadores Tumorais/genética , Proliferação de Células , Perfilação da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Células Tumorais Cultivadas
12.
Food Chem ; 361: 130139, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062461

RESUMO

Globally consumed kimchi is manufactured through fermenting cruciferous vegetables containing indole glucosinolates (IG). But few reports describe the IG metabolism during the fermentation. Here, we show that indole-3-carbinol (I3C), a breakdown product of IG, is transformed during the kimchi fermentation into 3,3'-diindolylmethane (DIM) and 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LTr1). LTr1 was found to kill the acute myeloid leukemia (AML) cells with FMS-like tyrosine kinase 3 (FLT3) receptor mutations, by inhibiting the FLT3 phosphorylation and the expression of downstream proteins (STAT5, ERK, and AKT). In the immune-depleted mice xenografted with human MV4-11 cells, LTr1 was demonstrated to reduce the tumor growth and synergize with sorafenib, an anti-AML agent in clinic. The work updates the chemical and biological knowledge about kimchi, and in particular establishes LTr1 as an FLT3 inhibitor that is effective and synergistic with sorafenib in treating AML.


Assuntos
Alimentos e Bebidas Fermentados , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Mutação , Fosforilação/efeitos dos fármacos , Sorafenibe/farmacologia
13.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070369

RESUMO

Folate receptor beta (FRß) is a folate binding receptor expressed on myeloid lineage hematopoietic cells. FRß is commonly expressed at high levels on malignant blasts in patients with acute myeloid leukemia (AML), as well as on M2 polarized tumor-associated macrophages (TAMs) in the tumor microenvironment of many solid tumors. Therefore, FRß is a potential target for both direct and indirect cancer therapy. We demonstrate that FRß is expressed in both AML cell lines and patient-derived AML samples and that a high-affinity monoclonal antibody against FRß (m909) has the ability to cause dose- and expression-dependent ADCC against these cells in vitro. Importantly, we find that administration of m909 has a significant impact on tumor growth in a humanized mouse model of AML. Surprisingly, m909 functions in vivo with and without the infusion of human NK cells as mediators of ADCC, suggesting potential involvement of mouse macrophages as effector cells. We also found that TAMs from primary ovarian ascites samples expressed appreciable levels of FRß and that m909 has the ability to cause ADCC in these samples. These results indicate that the targeting of FRß using m909 has the potential to limit the outgrowth of AML in vitro and in vivo. Additionally, m909 causes cytotoxicity to TAMs in the tumor microenvironment of ovarian cancer warranting further investigation of m909 and its derivatives as therapeutic agents in patients with FRß-expressing cancers.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Receptor 2 de Folato , Imunoterapia , Leucemia Mieloide Aguda , Proteínas de Neoplasias , Neoplasias Ovarianas , Animais , Células CHO , Cricetulus , Feminino , Receptor 2 de Folato/antagonistas & inibidores , Receptor 2 de Folato/imunologia , Células HL-60 , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/imunologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Células THP-1 , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070902

RESUMO

FLT3-mutated acute myeloid leukemia accounts for around 30% of acute myeloid leukemia (AML). The mutation carried a poor prognosis until the rise of tyrosine kinase inhibitors (TKIs). New potent and specific inhibitors have successfully altered the course of the disease, increasing the complete response rate and the survival of patients with FLT3-mutated AML. The aim of this article is to review all the current knowledge on these game-changing drugs as well as the unsolved issues raised by their use for fit and unfit FLT3-mutated AML patients. To this end, we analyzed the results of phase I, II, III clinical trials evaluating FLT3-TKI both in the first-line, relapse monotherapy or in combination referenced in the PubMed, the American Society of Hematology, the European Hematology Association, and the Clinicaltrials.gov databases, as well as basic science reports on TKI resistance from the same databases. The review follows a chronological presentation of the different trials that allowed the development of first- and second-generation TKI and ends with a review of the current lines of evidence on leukemic blasts resistance mechanisms that allow them to escape TKI.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Mieloide Aguda/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética , Ensaios Clínicos como Assunto , Bases de Dados Factuais , Expressão Gênica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Mutação , Recidiva , Transplante de Células-Tronco/métodos , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/metabolismo
15.
Cell Prolif ; 54(7): e13076, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34050566

RESUMO

CXCR4 is expressed on leukaemia cells and haematopoietic stem cells (HSCs), and its ligand stromal-derived factor 1 (SDF-1) is produced abundantly by stromal cells in the bone marrow (BM). The SDF-1/CXCR4 axis plays important roles in homing to and retention in the protective BM microenvironment of malignant leukaemia cells and normal HSCs. CXCR4 expression is regulated by multiple mechanisms and the level of CXCR4 expression on leukaemia cells has prognostic indications in patients with acute leukaemia. CXCR4 antagonists can mobilize leukaemia cells from BM to circulation, which render them effectively eradicated by chemotherapeutic agents, small molecular inhibitors or hypomethylating agents. Therefore, such combinational therapies have been tested in clinical trials. However, new evidence emerged that drug-resistant leukaemia cells were not affected by CXCR4 antagonists, and the migration of certain leukaemia cells to the leukaemia niche was independent of SDF-1/CXCR4 axis. In this review, we summarize the role of CXCR4 in progression and treatment of acute leukaemia, with a focus on the potential of CXCR4 as a therapeutic target for acute leukaemia. We also discuss the potential value of using CXCR4 antagonists as chemosensitizer for conditioning regimens and immunosensitizer for graft-vs-leukaemia effects of allogeneic haematopoietic stem cell transplantation.


Assuntos
Leucemia Mieloide Aguda/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores CXCR4/metabolismo , Benzilaminas/uso terapêutico , Quimiocina CXCL12/metabolismo , Ciclamos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Receptores CXCR4/antagonistas & inibidores , Transdução de Sinais , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico
16.
Medicine (Baltimore) ; 100(18): e25807, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950983

RESUMO

BACKGROUND: Runt-related transcription factor 1 (RUNX1) is one of the most frequently mutated genes in most of hematological malignancies, especially in acute myeloid leukemia. In the present study, we aimed to identify the key genes and microRNAs based on acute myeloid leukemia with RUNX1 mutation. The newly finding targeted genes and microRNA associated with RUNX1 may benefit to the clinical treatment in acute myeloid leukemia. MATERIAL/METHODS: The gene and miRNA expression data sets relating to RUNX1 mutation and wild-type adult acute myeloid leukemia (AML) patients were downloaded from The Cancer Genome Atlas database. Differentially expressed miRNAs and differentially expressed genes (DEGs) were identified by edgeR of R platform. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed by Metascape and Gene set enrichment analysis. The protein-protein interaction network and miRNA-mRNA regulatory network were performed by Search Tool for the Retrieval of Interacting Genes database and Cytoscape software. RESULTS: A total of 27 differentially expressed miRNAs (25 upregulated and 2 downregulated) and 561 DEGs (429 upregulated and 132 downregulated) were identified. Five miRNAs (miR-151b, miR-151a-5p, let-7a-2-3p, miR-363-3p, miR-20b-5p) had prognostic significance in AML. The gene ontology analysis showed that upregulated DEGs suggested significant enrichment in MHC class II protein complex, extracellular structure organization, blood vessel development, cell morphogenesis involved in differentiation, embryonic morphogenesis, regulation of cell adhesion, and so on. Similarly, the downregulated DEGs were mainly enriched in secretory granule lumen, extracellular structure organization. In the gene set enrichment analysis of Kyoto Encyclopedia of Genes and Genomes pathways, the RUNX1 mutation was associated with adherent junction, WNT signaling pathway, JAK-STAT signaling pathway, pathways in cancer, cell adhesion molecules CAMs, MAPK signaling pathway. Eleven genes (PPBP, APP, CCR5, HLA-DRB1, GNAI1, APLNR, P2RY14, C3AR1, HTR1F, CXCL12, GNG11) were simultaneously identified by hub gene analysis and module analysis. MicroRNA-363-3p may promote the development of RUNX1 mutation AML, targeting SPRYD4 and FNDC3B. In addition, the RUNX1 mutation rates in patient were obviously correlated with age, white blood cell, FAB type, risk(cyto), and risk(molecular) (P < .05). CONCLUSION: Our findings have indicated that multiple genes and microRNAs may play a crucial role in RUNX1 mutation AML. MicroRNA-363-3p may promote the development of RUNX1 mutation AML by targeting SPRYD4 and FNDC3B.


Assuntos
Carcinogênese/genética , Fibronectinas/genética , Leucemia Mieloide Aguda/genética , MicroRNAs/metabolismo , Proteínas Nucleares/genética , Biologia Computacional , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Conjuntos de Dados como Assunto , Feminino , Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/genética
17.
Nat Rev Clin Oncol ; 18(9): 577-590, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34006997

RESUMO

With rapid advances in sequencing technologies, tremendous progress has been made in understanding the molecular pathogenesis of acute myeloid leukaemia (AML), thus revealing enormous genetic and clonal heterogeneity, and paving the way for precision medicine approaches. The successful development of precision medicine for patients with AML has been exemplified by the introduction of targeted FLT3, IDH1/IDH2 and BCL-2 inhibitors. When used as single agents, these inhibitors display moderate antileukaemic activity. However, augmented clinical activity has been demonstrated when they are administered in combination with drugs with broader mechanisms of action targeting epigenetic and/or other oncogenic signalling pathways or with conventional cytotoxic agents. The development of immunotherapies has been hampered by the expression of antigens that are expressed by both leukaemic and non-malignant haematopoietic progenitor cells; nonetheless, a diverse range of immunotherapies are now entering clinical development. This myriad of emerging agents also creates challenges, such as how to safely combine agents with different mechanisms of action, the need to circumvent primary and secondary resistance, and new challenges in future clinical trial design. In this Review, we discuss the current state of precision medicine for AML, including both the potential to improve patient outcomes and the related challenges.


Assuntos
Leucemia Mieloide Aguda/terapia , Medicina de Precisão/tendências , Antineoplásicos/uso terapêutico , Epigênese Genética/fisiologia , Humanos , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Terapia de Alvo Molecular/métodos , Mutação , Medicina de Precisão/métodos
18.
Mol Cell ; 81(11): 2332-2348.e9, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33974912

RESUMO

Meningioma-1 (MN1) overexpression in AML is associated with poor prognosis, and forced expression of MN1 induces leukemia in mice. We sought to determine how MN1 causes AML. We found that overexpression of MN1 can be induced by translocations that result in hijacking of a downstream enhancer. Structure predictions revealed that the entire MN1 coding frame is disordered. We identified the myeloid progenitor-specific BAF complex as the key interaction partner of MN1. MN1 over-stabilizes BAF on enhancer chromatin, a function directly linked to the presence of a long polyQ-stretch within MN1. BAF over-stabilization at binding sites of transcription factors regulating a hematopoietic stem/progenitor program prevents the developmentally appropriate decommissioning of these enhancers and results in impaired myeloid differentiation and leukemia. Beyond AML, our data detail how the overexpression of a polyQ protein, in the absence of any coding sequence mutation, can be sufficient to cause malignant transformation.


Assuntos
Carcinogênese/genética , DNA Helicases/genética , Proteínas Intrinsicamente Desordenadas/genética , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/genética , Transativadores/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Animais , Sequência de Bases , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Cromatina/patologia , DNA Helicases/metabolismo , Elementos Facilitadores Genéticos , Feminino , Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Proteínas Intrinsicamente Desordenadas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , Peptídeos/genética , Peptídeos/metabolismo , Mapeamento de Interação de Proteínas , Estabilidade Proteica , Transporte Proteico , Transdução de Sinais , Análise de Sobrevida , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo
19.
Biochem Biophys Res Commun ; 562: 55-61, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34034094

RESUMO

Venetoclax is a highly selective BCL2 inhibitor widely used in the treatment of leukemia, especially chronic lymphocytic leukemia and acute myeloid leukemia (AML). However, long-term use of venetoclax may lead to secondary drug resistance, which constitutes an important obstacle to prolonging the duration of the therapeutic response. Here, we show that the acquired resistance to venetoclax in human AML cell lines depends on NF-κB activation rather than on the upregulation of anti-apoptotic BCL2L1 expression. Moreover, alkaliptosis induced by the small molecular compound JTC801, but not necroptosis and ferroptosis, inhibits the growth of venetoclax-resistant AML cells in vitro and in xenograft mouse models. Mechanistically, NF-κB-mediated CA9 downregulation is required for intracellular pH upregulation, thereby inducing alkaliptosis in venetoclax-resistant cells. These findings provide a new strategy to selectively remove venetoclax-resistant AML cells.


Assuntos
Álcalis/farmacologia , Apoptose , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide Aguda/patologia , NF-kappa B/metabolismo , Sulfonamidas/farmacologia , Aminoquinolinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Camundongos Nus , Proteína bcl-X/metabolismo
20.
Aging (Albany NY) ; 13(10): 14088-14108, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33999861

RESUMO

Caspase1 (CASP1) is a gene that encodes multiple proteins related to cell death. Nevertheless, the function of CASP1 in the pathogenesis of AML is still unclear. In the present study, a detailed analysis of cancer versus normal samples was performed to explore the relationship between CASP1 and leukemia. We used sequencing data from multiple cancer gene databases to analyze the gene expression and regulatory network of CASP1 in leukemia. We discovered that mRNA expression levels of CASP1 are increased in leukemia cell lines, especially in acute myelocytic leukemia (AML). Then, we verified the mRNA expression of CASP1 in AML clinical samples and observed significantly higher expression of CASP1 in relapsed AML patients. High CASP1 expression was associated with poor prognosis and CASP1 inhibition could impair the proliferation of AML cells. Related functional network identification suggests that CASP1 regulates apoptosis, immune and inflammatory response via pathways involving LYN, LCK, and the E2F family. These findings suggest that CASP1 probably contributes to the pathogenesis, and identify CASP1 as a factor for predicting the prognosis and as a therapeutic target of AML patients.


Assuntos
Caspase 1/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Caspase 1/metabolismo , Inibidores de Caspase/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Grupos de Populações Continentais , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Anotação de Sequência Molecular , Prognóstico , Proteínas Quinases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...