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1.
Artigo em Inglês | MEDLINE | ID: mdl-31645666

RESUMO

Mutations of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD) contribute to poor prognosis in cytogenetically normal acute myeloid leukemia (CN-AML). Chemotherapy has limited effect, while allogeneic hematopoietic stem cell transplantation (allo-HSCT) plus sorafenib maintenance is a promising protocol to improve their therapeutic outcome. However, the prognostic significance of FLT3-ITD mutant status remains controversial. To investigate this, we detected FLT3-ITD mutant ratio (high and low) and length (long and short) in enrolled 184 CN-AML patients without NPM1 mutation, and evaluated their impact on complete remission (CR), overall survival (OS), relapse-free survival (RFS) and relapse risk (RR) after chemotherapy or allo-HSCT plus sorafenib maintenance. Our studies showed that FLT3-ITD mutation had negative impact on chemotherapeutic response, OS and RFS in CN-AML patients. There was no significant difference in CR rate between high and low ratio, or long and short length. Increasing ITD mutant ratio and length were associated with decreasing OS, and long length had shorter RFS and higher RR than the short after chemotherapy. Allo-HSCT plus sorafenib maintenance was an effective strategy to improve RFS and decrease relapse probability in FLT3-ITD AML patients, and benefited to these regardless of mutant ratio, and those with long length instead of the short.

2.
Oncol Rep ; 42(6): 2333-2344, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638252

RESUMO

Gene mutations play an important role in the development and progression of AML1­ETO­positive acute myeloid leukemia (AE­AML). Nevertheless, the gene mutation profile in this subtype of leukemia remains unclear. In addition, the clinical and prognostic effects of different mutant genes may be underestimated. In the present study, gene sequencing was conducted at diagnosis and relapse with next­generation sequencing (NGS) in 64 patients with newly diagnosed AE­AML, and 44/64 (68.8%) patients were found to present with a median of 2 (1­10) recurrent mutations at diagnosis and 6/11 (54.5%) cases were found to present with genetic alterations at relapse. c­KIT mutation was the most common in this cohort, with an incidence of 27/64 (42.2%) at diagnosis, followed by ASXL1 (n=10, 15.6%), MET (n=8, 12.5%), MLH1 (n=6, 9.4%), TET2 (n=5, 7.8%), and FBXW7, TP53 and DNMT3A (n=5, 7.8%). Survival analysis showed that c­KIT (exon 8, 17) but not exon 10 adversely affected survival. In addition, ASXL1 and TP53 were poor impact factors for recurrence­free survival (RFS) (P<0.05), and ASXL1, MET, FBXW7 and TP53 had a negative impact on overall survival (OS) (P<0.05). Multivariate analysis showed that c­KIT (exon 8, 17) [RFS: hazard ratio (HR) 3.36, 95% confidence interval (CI) 1.54­7.34, P=0.002; OS: HR 2.84, 95% CI 1.20­6.71, P=0.018] and ASXL1 mutations (RFS: HR 3.13, 95% CI 1.34­7.32, P=0.009; OS: HR 3.94, 95% CI 1.62­9.61, P=0.003) were independent adverse factors for survival. Further, co­mutation of these two genes showed even worse effect on disease outcome. Collectively, additional gene mutations play critical role in AE­AML. C­KIT and ASXL1 mutations are the two most common mutations in this subtype of leukemia. C­KIT (exon 8, 17) but not exon 10, and also the ASXL1 mutation poorly affect the disease outcome of this disease.

3.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(3): 364-368, 2019 Mar 30.
Artigo em Chinês | MEDLINE | ID: mdl-31068313

RESUMO

OBJECTIVE: To analyze the clinical features of chronic myeloid leukemia (CML) with T315 I mutation (CML-T315I) and compare the effectiveness of different treatments. METHODS: We retrospectively analyzed the clinical data and outcomes of 19 patients with CML-T315I receiving different treatments. The T315 I mutations in these patients were detected by examination of BCR-ABL kinase domain (KD) mutation by RTQ-PCR and Sanger sequencing. The relapse following the treatments, defined as hematological, cytogenetic and molecular biological recurrences, were analyzed in these patients. RESULTS: Of the 19 patients with CML-T315I, 14 (73.7%) were in CML-CP stage at the initial diagnosis, and 13 (81.2%) were high-risk patients based on the Sokal scores. All the 19 patients were treated with TKI after the initial diagnosis, and during the treatment, 15 (78.9%) patients were found to have additional chromosomal aberrations, and 10 (52.6%) had multiple mutations; 13 (68.4%) of the patients experienced disease progression (accelerated phase/blast crisis) before the detection of T315I mutation, with a median time of 40 months (5-120 months) from the initial diagnosis to the mutation detection. After detection of the mutation, 12 patients were treated with ponatinib and 7 were managed with the conventional chemotherapy regimen, and their overall survival rates at 3 years were 83.3% and 14.2%, respectively (P < 0.001). CONCLUSIONS: CML patients resistant to TKI are more likely to have T315I mutations, whose detection rate is significantly higher in the progressive phase than in the chronic phase. These patients often have additional chromosomal aberrations and multiple gene mutations with poor prognoses and a high recurrence rate even after hematopoietic stem cell transplantation. Long-term maintenance therapy with ponatinib may improve the prognosis and prolong the survival time of the patients.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl , Humanos , Imidazóis , Mutação , Piridazinas , Estudos Retrospectivos
4.
Biomed Rep ; 9(3): 227-232, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30271598

RESUMO

The present study retrospectively analyzed 96 newly diagnosed acute promyelocytic leukemia (APL) patients with low-intermediate mortality risk to identify the optimum timing to initiate cytotoxic chemotherapy following all-trans retinoic acid (ATRA) administration. Based on white blood cell (WBC) at chemotherapy initiation, the patients were divided into three groups: low WBC (WBC count ≤4×109/l), intermediate WBC (WBC count >4×109/l and <15×109/l) and high WBC group (WBC count ≥15×109/l). According to the period from ATRA commencement to chemotherapy, 96 patients were further divided into two groups: ≤3 days group (chemotherapy within 3 days of ATRA) and >3 days group (chemotherapy >3 days after ATRA). Clinical effects were compared by univariate analysis and multivariate analyses. The incidence rate of differentiation syndrome (DS; also termed retinoic acid syndrome) was 0.0, 11.1 and 40.0% in the low, intermediate and high WBC groups, respectively (P<0.001); complete remission (CR) rate was 90.5, 100.0 and 73.3%, respectively (P<0.001); and the rate of early mortality (defined as fatality during induction treatment) was 4.8, 0.0 and 26.7%, respectively (P<0.001). No differences were identified in clinicolaboratory parameters between the ≤3 days and >3 days groups, except in time to achieve CR (P=0.004) and rate of bleeding related to chemotherapy (P=0.009), both being higher in the >3 days group. Multivariate analyses indicated WBC count at chemotherapy was the only independent risk factor for the occurrence of DS [P=0.002; odds ratio (OR) =1.058, 95% confidence interval (CI) =1.021-1.095] and early mortality (P=0.036; OR =1.036, 95% CI =1.002-1.070). For newly diagnosed APL patients with low-intermediate risk, chemotherapy initiation should be recommended until WBC count rises to between 4×109/l and 15×109/l during induction treatment.

5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 26(3): 678-683, 2018 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-29950203

RESUMO

OBJECTIVE: To explore the influence of FLT3-ITD mutation and ITD length on the overall survival (OS) and relapse free survival(RFS) in patients with non-M3 acute myeloid leukemia. METHODS: Clinical features and therapeutic effect were retrospectively analyzed in 75 AML patients with FLT3-ITD mutation and 76 FLT3-ITD- AML patients with a normal karotype from June 2011 to April 2016. Genomic DNA was amplified by PCR, and FLT3-ITD mutation length was analyzed by DNA sequencing in 40 patients. RESULTS: AML patients with FLT3-ITD mutation had higher WBC count and the ratio of BM blast cells at initial diagnosis was also higher than those in AML patients without FLT3-ITD mutation (95.13 vs 10.85)(P<0.01); 72% vs 59%(P<0.01). The CR rates in AML patients with FLT3-ITD mutation less than those in AML patients without FLT3-ITD mutation(70.42% vs 94.7%)(P<0.01). OS (P<0.01) and RFS (P<0.01) were significantly increased in patients with AML who received allo-HSCT as compared with the patients who received consolidation chemotherapy and similar to AML patients without FLT3-ITD mutation who received HSCT. Patients with maintenance sorafenib after HSCT had longer OS (P<0.05) and RFS (P<0.05) than controls. ITDs exceeding 60 bp in length were associated with decreasing OS as compared with shorter ITD in AML patients with FLT3-ITD mutation (P<0.05). OS and RFS were similar among the 2 groups receiving consolidation chemotherapy. Besides, the patients with allo-HSCT had shorter ITDs and longer OS than ITDs exceeding 60 bp (P<0.05) and similar to AML patients without FLT3-ITD mutation. CONCLUSION: AML patients with FLT3-ITD mutation has poorer outcome, among which the prognosis was worse in patients with ITD exceeding 60 bp, and the chemotherapy alone can not improve the prognosis of FLT3-ITD+. Allo-HSCT is an effective treatment for AML patients with FLT3-ITD mutation; Sorafenib appears to be an effective maintenance therapy after allo-HSCT in FLT3-ITD AML.


Assuntos
Mutação , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda , Proteínas de Fusão Oncogênica , Prognóstico , Estudos Retrospectivos , Tirosina Quinase 3 Semelhante a fms
6.
Oncol Lett ; 15(1): 917-925, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29399155

RESUMO

Amyloid precursor protein (APP) has been reported to be highly expressed in acute myeloid leukemia (AML)1-eight-twenty one (ETO)-positive AML. In the present study, the clinical and prognostic significance of APP expression was assessed in 65 patients with AML1-ETO-positive AML using reverse transcription-quantitative polymerase chain reaction. The patients were divided into an APP-high expression (APP-H) group (n=32) and an APP-low expression (APP-L) group (n=33) according to the cut-off value of APP relative expression, which was calculated by receiver operating characteristic curve analysis. It was observed that C-KIT mutations (14/32 vs. 3/33, P=0.009), white blood cell count (median, 23.2×109 vs. 12.4×109 cells/l; P=0.011) and bone marrow cellularity (median, 91.0 vs. 84.0%; P=0.039) and incidence of extramedullary leukemia (11/32 vs. 3/33, P=0.013) were all significantly increased in the APP-H group compared with the APP-L group. Furthermore, significantly lower rate of cumulative two-cycle complete remission (83.9 vs. 100%, P=0.016), major molecular remission following two courses of consolidation (34.5 vs. 71.4%, P=0.005), and poorer relapse-free survival (RFS) (33.5±5.2% vs. 76.3±6.9%, P<0.001) and overall survival (OS) (44.5±7.0% vs. 81.9±5.8%, P=0.002) were associated with APP overexpression. Multivariate analysis revealed that APP overexpression was a significant adverse factor affecting both RFS and OS. Taken together, these data suggest that APP may be correlated with C-KIT mutations and involved in leukemia cell proliferation, and its overexpression has an adverse effect on the prognosis in AML1-ETO-positive AML.

7.
Clin Cancer Res ; 24(10): 2417-2429, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29463558

RESUMO

Purpose: Wnt/ß-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases ß-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKI) are used clinically to treat FLT3-mutated AML patients, but with limited efficacy. We investigated the antileukemia activity of combined Wnt/ß-catenin and FLT3 inhibition in FLT3-mutant AML.Experimental Design: Wnt/ß-catenin signaling was inhibited by the ß-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib. Treatments on apoptosis, cell growth, and cell signaling were assessed in cell lines, patient samples, and in vivo in immunodeficient mice by flow cytometry, Western blot, RT-PCR, and CyTOF.Results: We found significantly higher ß-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone marrow-resident leukemic cells compared with circulating blasts. Disrupting Wnt/ß-catenin signaling suppressed AML cell growth, induced apoptosis, abrogated stromal protection, and synergized with TKIs in FLT3-mutated AML cells and stem/progenitor cells in vitro The aforementioned combinatorial treatment improved survival of AML-xenografted mice in two in vivo models and impaired leukemia cell engraftment. Mechanistically, the combined inhibition of Wnt/ß-catenin and FLT3 cooperatively decreased nuclear ß-catenin and the levels of c-Myc and other Wnt/ß-catenin and FLT3 signaling proteins. Importantly, ß-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells.Conclusions: Disrupting Wnt/ß-catenin signaling exerts potent activities against AML stem/progenitor cells and synergizes with FLT3 inhibition in FLT3-mutant AML. These findings provide a rationale for clinical development of this strategy for treating FLT3-mutated AML patients. Clin Cancer Res; 24(10); 2417-29. ©2018 AACR.

8.
Medicine (Baltimore) ; 96(51): e9324, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29390508

RESUMO

The aim of this study was to identify risk factors for early death (ED) in acute promyelocitic leukemia (APL) patients.Clinical records of 49 APL patients who suffered ED were divided into 4 groups: death before treatment or within the first 3 days (immediate death; iED group), death during treatment at least 3 days after commencement (ED after treatment), low/intermediate risk, and high-risk groups.White blood cell (WBC) count, high-risk cases, prothrombin time (PT) prolongation, international society on thrombosis and hemostasis (ISTH) scores (P < .05), bleeding (P = .05), and death due to severe hemorrhage (P = .010) were higher in iED group than ED after treatment. And the time from onset to initial hospitalization or death was significantly shorter (P < .05) in iED patients. LDH level (P = .002), PT prolongation (P = .014), and incidence of grades 3 or 4 bleeding (P = .049) were higher in high-risk group than in ED and low/intermediate-risk groups, while the times from onset to the initial hospitalization or death were lower for ED patients in high-risk group (P = .037).We found that different types of EDs have different clinical features. A high WBC count contributes to the occurrence of more ED, which is usually not associated with delay of diagnosis and hospitalization. Current therapeutic strategies to reduce the incidence of ED in these cases are not adequate and will benefit from focused research attention.


Assuntos
Leucemia Promielocítica Aguda/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Feminino , Hemoglobinas/análise , Hemorragia/mortalidade , Humanos , L-Lactato Desidrogenase/sangue , Leucemia Promielocítica Aguda/sangue , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Tempo de Protrombina , Fatores de Tempo , Adulto Jovem
9.
Oncol Rep ; 36(3): 1626-32, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27460334

RESUMO

It has been reported that amyloid precursor protein (APP) promotes cell proliferation and metastasis in various types of solid cancers. In our previous study, we showed that APP is highly expressed and regulates leukemia cell migration in AML1­ETO-positive (AE) leukemia. Whether APP is involved in the regulation of AE leukemia cell proliferation or apoptosis is unclear. In the present study we focused on the correlation of APP with c-KIT mutation/overexpression and cell proliferation and apoptosis in AE leukemia. APP and c-KIT expression detected by quantitative real-time (qPCR) method, and c-KIT mutations screened using PCR in bone marrow cells from 65 patients with AE leukemia before their first chemotherapy, were simultaneously assessed. Furthermore, the Kasumi-1 cell line was chosen as the cell model, and the APP gene was knocked down using siRNA technology. The correlation of cell cycle distribution and apoptosis and c-Kit expression with APP expression levels, as well as the regulation of the PI3K/AKT signaling pathway by APP were analyzed in the Kasumi-1 cell line. The results showed that peripheral white blood cell counts (P=0.008) and bone marrow cellularity (P=0.031), but not bone marrow blasts, were correlated with APP expression. Moreover, the patients with APP high expression had a significantly higher incidence of c-KIT mutations (P<0.001) and increased levels of c-KIT expression (P=0.001) and poorer disease outcome. In the Kasumi-1 cell line, as compared with the wild-type and negative control cells, cell apoptosis, both early (P<0.001) and late (P<0.001), was significantly increased when the APP gene was knocked down, concomitant with reduced levels of anti-apoptotic protein Bcl-2 and increased levels of caspase-3 and -9, however, no apparent change was observed in the cell cycle distribution (P>0.05). Moreover, the knockdown of APP markedly decreased c-KIT expression at both the transcription (as evidenced by qPCR analysis) and translation (as confirmed by CD117 assay and western blot analysis) levels, as well as p-AKT and its downstream targets including NF-κB, p53 and Bcl-2. In conclusion, APP may cooperate with c-KIT mutation/overexpression in the regulation of cell apoptosis but not proliferation in AE leukemia via the PI3K/AKT signaling pathway.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Apoptose/fisiologia , Leucemia Mieloide Aguda/patologia , Transdução de Sinais/fisiologia , Adolescente , Adulto , Idoso , Western Blotting , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteína 1 Parceira de Translocação de RUNX1 , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição/genética , Regulação para Cima , Adulto Jovem
10.
Exp Ther Med ; 11(5): 2061-2065, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27168851

RESUMO

Low concentrations of imatinib (IM) in bone marrow cells have been linked with poor prognosis in patients with chronic myeloid leukemia (CML), which may be caused by the emergence of ATP-binding cassette transporter B1 (ABCB1) mutations. The aim of present study was to investigate how clinical outcomes vary among patients with different single nucleotide polymorphisms (SNPs) of ABCB1. A total of 48 adult patients with CML and higher than median ABCB1 mRNA levels were selected for testing of ABCB1 SNPs. In 28 of the 48 patients, the IM concentration and expression levels of human organic cation transporter 1 (hOCT1) and ABCB1 in bone marrow mononuclear cells (BMMCs) were also tested. Correlations between treatment outcomes and IM concentration or the SNP status of ABCB1 were analyzed. Patients were classified by therapeutic response as major molecular response (MMR) (n=11), complete cytogenetic response (CCyR) (n=19) and non-CCyR (n=18) groups. It was found that the concentration of IM in BMMCs of the CCyR group was significant higher than that of the resistant groups (P=0.013). In addition, the IM concentration was positively correlated with the expression of hOCT1 mRNA (R=0.456, P=0.033), but negatively correlated with the expression of ABCB1 mRNA (R=-0.491, P=0.015). Furthermore, the mRNA expression level of ABCB1 was not associated with therapeutic response, but SNPs of the ABCB1 gene were associated with the response to IM. In conclusion, the concentration of IM in BMMCs may be regulated by the ABCB1 gene, and SNPs of the ABCB1 gene predict the therapeutic response to IM in patients with CML.

11.
Oncotarget ; 7(22): 33004-15, 2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-27105509

RESUMO

Total body irradiation combined with chemotherapy is currently the most effective procedure as a preparative myeloablative regimen. However, resistance to radiotherapy and chemotherapy in refractory acute myeloid leukemia is associated with short-time recurrence after allogeneic hematopoietic stem cell transplantation. To address this issue, we used three cell lines, HL60, HL60/ADR (adriamycin-resistant cells), and HL60/RX (a radiation-resistant cell line established from HL60 cells), as cellular models to investigate the mechanism of the Hedgehog (Hh) signaling pathway resulting in radioresistance, and the efficacy of LDE225 (an inhibitor of the Hh pathway) to enhance radiation sensitivity. Our results indicated that HL60/RX and HL60/ADR cells showed an increased in radioresistance and elevated activity of Hh pathway proteins compared with HL60 cells (P<0.001). In addition, LDE225 significantly reduced clonogenic survival with a sensitivity enhancement ratio (SER) of 1.283 for HL60/ADR and 1.245 for HL60/RX cells. The combination of LDE225 with irradiation significantly increased radiation-induced apoptosis and expression of γ-H2AX and BAK compared with single-treatment groups in both HL60/RX and HL60/ADR cells (P<0.001). In vivo, the combination of LDE225 with irradiation exerted a significant antitumor effect compared with the control and single agents in HL60/RX- and HL60/ADR-xenografted mouse models (P<0.001). Furthermore, our data obtained from western blot and IHC analyses showed that the activation of pAKT and NF-kB was reduced by LDE225 treatment in both HL60/ADR and HL60/RX cells. This demonstrates that the Gli-1/PI3K/AKT/NF-kB pathway plays a key role in resistance to radiation, and that inhibition of the Hh pathway sensitizes cells to radiation by overcoming radioresistance.


Assuntos
Leucemia Mieloide Aguda/radioterapia , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína GLI1 em Dedos de Zinco/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Células HL-60 , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tolerância a Radiação , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Tumour Biol ; 37(8): 11409-20, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27000755

RESUMO

Accumulating evidence indicates that enhancer of zeste homolog 2 (EZH2) promotes the metastatic ability of solid tumors, but the role of EZH2 in extramedullary infiltration (EMI) in acute myeloid leukemia (AML) has not been thoroughly explored. In the present study, we investigated the possible association between EZH2 and EMI. We found that the messenger RNA (mRNA) and protein expression levels of EZH2 in AML patients were both significantly higher than in idiopathic thrombocytopenic purpura (ITP) patients. Furthermore, a positive correlation between EZH2 mRNA expression and percentage of peripheral blood blasts wa s found in AML patients (r = 0.404, p = 0.009). The migratory capacities of Kasumi-1 and HL-60, which both show a high level of EZH2 expression, were markedly higher than those of U937 and KG-1α. In contrast, silencing of EZH2 resulted in reduction in proliferation and migration ability and an increase in apoptosis. The latter observation was accompanied by reduced expression of associated proteins p-ERK, p-cmyc, and matrix metalloproteinase 2 (MMP-2) and an increase in epithelial cadherin (E-cadherin). These data suggest that higher expression of EZH2 may be associated with extramedullary infiltration in acute myeloid leukemia and affect pathogenesis via activation of the p-ERK/p-cmyc/MMP-2 and E-cadherin signaling pathways.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/biossíntese , Leucemia Mieloide Aguda/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Movimento Celular/fisiologia , Criança , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Transdução de Sinais/fisiologia , Adulto Jovem
13.
Mol Clin Oncol ; 3(5): 1139-1144, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26623066

RESUMO

Decitabine (5-aza-2'-deoxycytidine; DAC) is a well-tolerated alternative to aggressive chemotherapy for leukemia, which induces differentiation and apoptosis of leukemic cells as a DNA hypomethylating agent. The aim of the present study was to investigate the feasibility of DAC sequentially combined with chemotherapy to reverse drug resistance. HL-60/ADR multidrug-resistant leukemia cells cultured in 96-well plates were pretreated with DAC for 72 h; varying concentrations of aclacinomycin (ACLA) were then added to the wells, cell proliferation was tested using the Cell Counting Kit-8 assay, and DNA methyltransferase 1 (DNMT1) protein expression was detected by western blot analysis. Furthermore, we analyzed the therapeutic efficacy in 7 patients with high-risk acute myeloid leukemia (AML) receiving induction therapy with DAC sequentially combined with cytarabine, ACLA and granulocyte-colony stimulating factor (CAG regimen). The proliferation inhibition rate of HL-60/ADR cells treated with DAC at concentrations of 0.5 and 1.0 µmol/l sequentially combined with ACLA was significantly higher compared with that with ACLA alone (P<0.001 for both). DNMT1 expression was significantly repressed following treatment with 1.0 µmol/l DAC. Of the 11 patients, 8 (72.7%) received induction therapy with DAC sequentially combined with CAG agents and achieved complete remission (CR) after 2 cycles of treatment; however, 3 (27.3%) patients did not achieve remission. Myelosuppression was observed in all 11 patients and pulmonary infections developed in 9 patients (81.8%) during the course of the study. At the last follow-up, 7 of the 8 patients who achieved CR remained in remission. The median follow-up was 6 months (range, 3-18 months). Therefore, pretreatment with DAC may increase the sensitivity of HL-60/ADR cells to ACLA via the epigenetic modulation of demethylation and the sequential administration of DAC and CAG regimen appears to be safe and effective for the treatment of patients with high-risk AML.

14.
Oncotarget ; 6(32): 33612-22, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26384351

RESUMO

In this study, we investigated the effect of pre-treatment with demethylating agent decitabine on susceptibility to chemotherapeutic drugs in HL60/ADR, Kasumi-1 and primary AML cells. Cytotoxic effect was increased by decitabine through activation of p53 and inhibition of c-Myc, Survivin and Bcl-2. We demonstrated in clinic that combination of decitabine and HAA consisting of harringtonine, aclarubicin and cytarabine was effective and safe to treat patients with refractory, relapsed or high-risk AML. Decitabine prior to HAA regimen improved the first induction complete response rate, and significantly prolonged overall survival and disease-free survival in these patients compared with HAA alone. These findings support clinic protocols based on decitabine prior to chemotherapy to overcome resistance and improve therapeutic efficacy in AML patients.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/análogos & derivados , Leucemia Mieloide Aguda/tratamento farmacológico , Aclarubicina/administração & dosagem , Adolescente , Adulto , Antimetabólitos Antineoplásicos/administração & dosagem , Azacitidina/administração & dosagem , Azacitidina/farmacologia , Linhagem Celular Tumoral , Citarabina/administração & dosagem , Decitabina , Intervalo Livre de Doença , Feminino , Células HL-60 , Harringtoninas/administração & dosagem , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Resultado do Tratamento , Adulto Jovem
15.
Med Sci Monit ; 21: 2257-65, 2015 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-26238068

RESUMO

BACKGROUND: The influence of different non-myeloablative conditioning regimens on clinical outcome remains undefined. MATERIAL AND METHODS: We retrospectively analyzed the hematopoietic reconstitution, graft-versus-host disease (GVHD), and quality of life (QOL) in 56 patients with hematologic malignancies who underwent non-myeloablative stem cell transplantation (NST) with a conditioning regimen based on anti-thymocyte globulin (ATG), followed by donor lymphocyte infusion (n=24), or Fludarabine (FLU) (n=32). Hematopoietic stem cells were derived from low-resolution HLA-matched identical sibling donors. RESULTS: The blood type transformation and platelet reconstitution presented significantly earlier in the FLU group than the ATG group (P<0.05). Within 100 days post-transplantation, the incidence of grade I-IV acute GVHD was significantly lower in the ATG group than the FLU group (P<0.05). After 100 days post-transplant, extensive chronic GVHD (cGVHD) was more prevalent in the ATG group than the FLU group (P<0.05). There were lower cumulative risk of relapse and higher non-relapse-related mortality in the ATG group, but better QOL in the FLU group within 24 months, and no difference in 3-year disease-free survival (DFS) or overall survival (OS) between the 2 groups (P>0.05). CONCLUSIONS: The FLU-based conditioning regimen improved hematopoietic reconstitution and decreased extensive cGVHD, but there was no difference in 3-year DFS or OS between the 2 groups.


Assuntos
Soro Antilinfocitário/uso terapêutico , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Agonistas Mieloablativos/uso terapêutico , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Adolescente , Adulto , Criança , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Estudos Retrospectivos , Vidarabina/uso terapêutico , Adulto Jovem
16.
Dis Markers ; 2015: 382186, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25944974

RESUMO

Mixed phenotype acute leukemia (MPAL) is a complex entity expressing both lymphoid and myeloid immunophenotyping. In the present study, 47 MPAL, 60 lymphoid antigen-positive acute myeloid leukemia (Ly(+)AML), and 90 acute myeloid leukemia with common myeloid immunophenotype (Ly(-)AML) patients were investigated. We found that, in MPAL patients, there were high proportions of blast cells in bone marrow and incidence of hepatosplenomegaly, lymphadenopathy, and Philadelphia chromosome. The overall survival (OS) and relapse-free survival (RFS) in MPAL patients were significantly shorter than those in Ly(+)AML and Ly(-)AML. With regard to the patients with normal karyotype only, the OS and RFS of MPAL were significantly lower than those of the Ly(+)AML and Ly(-)AML; but there were no significant differences in OS and RFS among the patients with complex karyotype. The OS rates of 3 groups with complex karyotype were lower than those of patients with normal karyotype. In Cox multivariate analysis, complex karyotype was an independent pejorative factor for both OS and RFS. Therefore, MPAL is confirmed to be a poor-risk disease while Ly(+)AML does not impact prognosis. Complex karyotype is an unfavorable prognosis factor in AML patients with different immunophenotype. Mixed immunophenotype and complex karyotype increase the adverse risk when they coexist.


Assuntos
Antígenos CD/imunologia , Antígenos Ly/imunologia , Cariótipo , Leucemia Aguda Bifenotípica/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Células da Medula Óssea/patologia , Criança , Pré-Escolar , China , Feminino , Humanos , Imunofenotipagem , Leucemia Aguda Bifenotípica/genética , Leucemia Aguda Bifenotípica/imunologia , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida
17.
Dis Markers ; 2014: 421906, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25045197

RESUMO

CD2+, CD34+, and CD56+ immunophenotypes are associated with poor prognoses of acute promyelocytic leukemia (APL). The present study aimed to explore the role of APL immunophenotypes and immune markers as prognostic predictors on clinical outcomes. A total of 132 patients with de novo APL were retrospectively analyzed. Immunophenotypes were determined by flow cytometry. Clinical features, complete remission (CR), relapse, and five-year overall survival (OS) rate were assessed and subjected to multivariate analyses. The CD13+CD33+HLA-DR-CD34- immunophenotype was commonly observed in patients with APL. Positive rates for other APL immune markers including cMPO, CD117, CD64, and CD9 were 68.7%, 26%, 78.4%, and 96.6%, respectively. When compared with patients with CD2- APL, patients with CD2+ APL had a significantly higher incidence of early death (50% versus 15.7%; P = 0.016), lower CR rate (50% versus 91.1%; P = 0.042), and lower five-year OS rate (41.7% versus 74.2%; P = 0.018). White blood cell (WBC) count before treatment was found to be the only independent risk factor of early death, CR failure, and five-year mortality rate. Flow cytometric immunophenotype analysis can facilitate prompt APL diagnosis. Multivariate analysis has demonstrated that WBC count before treatment is the only known independent risk factor that predicts prognosis for APL in this study population.


Assuntos
Antígenos CD/sangue , Biomarcadores Tumorais/sangue , Antígenos HLA-DR/sangue , Leucemia Promielocítica Aguda/sangue , Adolescente , Adulto , Idoso , Antígenos CD/imunologia , Biomarcadores Tumorais/imunologia , Feminino , Antígenos HLA-DR/imunologia , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/imunologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico
18.
PLoS One ; 9(1): e84150, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24416201

RESUMO

Numerous factors impact on the prognosis of acute myeloid leukemia (AML), among which molecular genetic abnormalities are developed increasingly, however, accurate prediction for newly diagnosed AML patients remains unsatisfied. For further improving the prognosis evaluation system, we investigated the transcripts levels of PDCD7, FIS1, FAM3A, CA6, APP, KLRF1, ATCAY, GGT5 and Ang2 in 97 AML patients and 30 non-malignant controls, and validated using the published microarray data from 225 cytogenetically normal AML (CN-AML) patients treated according to the German AMLCG-1999 protocol. Real-time quantitative polymerase chain reaction and western blot were carried out, and clinical data were collected and analyzed. High Ang2 and FIS1 expression discriminated the CR rate of AML patients (62.5% versus 82.9% for Ang2, P = 0.011; 61.4% versus 82.2% for FIS1, P = 0.029). In CN-AML, patients with high FIS1 expression were more likely to be resistant to two courses of induction (P = 0.035). Overall survival (OS) and relapse-free survival (RFS) were shorter in CN-AML patients with high PDCD7 expression (P<0.001; P = 0.006), and PDCD7 was revealed to be an independent risk factor for OS in CN-AML (P = 0.004). In the analysis of published data from 225 CN-AML patients, PDCD7 remained independently predicting OS in CN-AML (P = 0.039). As a conclusion, Ang2 and FIS1 seem related to decreased CR rate of AML patients, and PDCD7 is associated with shorter OS and RFS in CN-AML. Hence, PDCD7, Ang2 and FIS1 may indicate a more aggressive form and poor prognosis of AML.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Biomarcadores Tumorais/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Fatores de Transcrição/genética , Proteínas de Transporte Vesicular/genética , Adolescente , Adulto , Idoso , Proteínas Reguladoras de Apoptose/metabolismo , Estudos de Casos e Controles , Análise Citogenética , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Immunoblotting , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas Mitocondriais/metabolismo , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Receptores de Células Matadoras Naturais/genética , Receptores de Células Matadoras Naturais/metabolismo , Recidiva , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sobrevida , Fatores de Transcrição/metabolismo , Resultado do Tratamento , Proteínas de Transporte Vesicular/metabolismo , Adulto Jovem
19.
Cancer Lett ; 326(2): 135-42, 2012 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-22863538

RESUMO

In this study, we investigated the synergistic effects of panobinostat and bortezomib on adriamycin-resistant HL60/ADR cells and refractory acute myelogenous leukemia (AML) primary cells. Combination of both agents had synergistic cytotoxicity on these cells, and increased the sensitivity of HL60/ADR cells to adriamycin. Panobinostat plus bortezomib was shown to modulate multiple apoptotic and drug metabolic related molecules, including activation of caspases, down-regulation of XIAP, Bcl-2 and MRP1. These effects were likely to be mediated via inhibition of AKT and NF-κB pathways. These findings provide evidence for clinic protocols using panobinostat and borezomib to overcome drug resistance in refractory AML patients.


Assuntos
Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Indóis/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazinas/uso terapêutico , Acetilação , Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Bortezomib , Caspases/metabolismo , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Células HL-60 , Humanos , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Leucemia Mieloide Aguda/patologia , Panobinostat , Poli(ADP-Ribose) Polimerases/metabolismo , Proteólise , Pirazinas/farmacologia
20.
Zhonghua Yi Xue Za Zhi ; 91(32): 2287-92, 2011 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-22094098

RESUMO

OBJECTIVE: To investigate the effects of everolimus (RAD001) or plus panobinostat (LBH589) on the proliferation, apoptosis and drug resistance in chemoresistant acute myeloid leukemic cells. METHODS: HL-60/ADM cells were treated with RAD001 alone or with LBH589. Proliferation and apoptosis were evaluated by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, Hoechst33342 and AnnexinV-FITC/PI stain. The altered expressions of multidrug resistance-associated protein 1 (MRP1) and intercellular adriamycin accumulation were analyzed by flow cytometry. The change in protein level was analyzed by Western blot. RESULTS: Effective proliferative inhibition and apoptotic induction in HL60/ADM cells were observed in the treatment of 10 - 50 µmol/L RAD001. The maximal effect was shown for the concentration of 30 µmol/L RAD001 at 48 and 72 hours. The inhibition ratio remained unchanged with the adjustment of drug doses (P < 0.05). Moreover, there was no synergistic effects in the treatment with different concentration of RAD001 and LBH589 (CI ≥ 1.0). A down-regulation of MRP1 (93.9% ± 4.2% vs 79.10 ± 3.28%) and an up-regulation of adriamycin (8.53 ± 0.68% vs 15.37% ± 1.46%) were induced by the treatment with 10 µmol/L RAD001 (both P < 0.01). RAD001 inhibited the p53-dependent expression of MRP1 via an inhibition of phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling pathway. CONCLUSION: The combined treatment of RAD001 and LBH589 has no synergistically inhibitory effect on HL60/ADM cells. But the sole treatment of RAD001 may inhibit proliferation, induce apoptosis and accumulate intercellular adriamycin through a down-regulated expression of MRP1 in HL60/ADM cells via an inhibition of PI3K/Akt/mTOR signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ácidos Hidroxâmicos/farmacologia , Sirolimo/análogos & derivados , Everolimo , Células HL-60/efeitos dos fármacos , Humanos , Indóis , Panobinostat , Sirolimo/farmacologia
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