scholarly journals Significance of PARP1 expression levels in patients with acute myeloid leukemia

2018 ◽  
Vol 29 ◽  
pp. ix87 ◽  
Author(s):  
H. Pashaiefar ◽  
M. Yaghmaie ◽  
J. Tavakkoly-Bazzaz ◽  
S.H. Ghaffari ◽  
K. Alimoghaddam ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Expression Levels ◽  
Acute Myeloid

scholarly journals Decitabine shows anti-acute myeloid leukemia potential via regulating the miR-212-5p/CCNT2 axis

2020 ◽  
Vol 15 (1) ◽  
pp. 1013-1023
Author(s):  
Lina Xing ◽  
Jinhai Ren ◽  
Xiaonan Guo ◽  
Shukai Qiao ◽  
Tian Tian
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Viability ◽  
Cell Apoptosis ◽  
Myeloid Leukemia ◽  
Luciferase Reporter ◽  
Expression Levels ◽  
Proliferation And Apoptosis ◽  
Polymerase Chain ◽  
The Relationship ◽  
Acute Myeloid

AbstractPrevious research has revealed the involvement of microRNA-212-5p (miR-212-5p) and cyclin T2 (CCNT2) in acute myeloid leukemia (AML). However, whether the miR-212-5p/CCNT2 axis is required for the function of decitabine in AML has not been well elucidated. Quantitative reverse transcription-polymerase chain reaction was used to examine enrichment of miR-212-5p. The relationship between CCNT2 and miR-212-5p was verified by the luciferase reporter assay. Cell apoptosis was evaluated by flow cytometry and western blot. CCK-8 assay was performed to determine cell viability. Decitabine significantly repressed cell viability, while promoted cell apoptosis. Meanwhile, the expression levels of cyclinD1, CDK4, and Bcl-2 were suppressed in cells with decitabine exposure, but Bax and caspase-3 expression levels were upregulated. Besides, miR-212-5p upregulation had the similar function with decitabine in AML cell proliferation and apoptosis. Subsequently, restoration of CCNT2 attenuated miR-212-5p overexpression-induced effects in Kasumi-1 and SKNO-1 cells. In addition, miR-212-5p depletion reversed decitabine-induced CCNT2 downregulation. The miR-212-5p/CCNT2 axis had an implication in the anti-leukemic effect of decitabine in AML.

Clinical impact of KMT2C and SPRY4 expression levels in intensively treated younger adult acute myeloid leukemia patients

2017 ◽  
Vol 99 (6) ◽  
pp. 544-552 ◽  
Author(s):  
Sabine Kayser ◽  
Maximilian Feszler ◽  
Julia Krzykalla ◽  
Matthias Schick ◽  
Michael Kramer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Impact ◽  
Expression Levels ◽  
Acute Myeloid

scholarly journals A proteomic approach to understand the clinical significance of acute myeloid leukemia-derived extracellular vesicles reflecting essential characteristics of leukemia

2020 ◽  
pp. mcp.RA120.002169
Author(s):  
Ka-Won Kang ◽  
Hyoseon Kim ◽  
Woojune Hur ◽  
Jik-han Jung ◽  
Su Jin Jeong ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Extracellular Vesicle ◽  
The Cancer Genome Atlas ◽  
Enzyme Linked Immunosorbent Assay ◽  
Expression Levels ◽  
Proteomic Approach ◽  
Cancer Genome Atlas ◽  
Acute Myeloid

Extracellular vesicle (EV) proteins from acute myeloid leukemia (AML) cell lines were analyzed using mass spectrometry. The analyses identified 2450 proteins, including 461 differentially expressed proteins (290 upregulated and 171 downregulated). CD53 and CD47 were upregulated and were selected as candidate biomarkers. The association between survival of patients with AML and the expression levels of CD53 and CD47 at diagnosis was analyzed using mRNA expression data from The Cancer Genome Atlas database. Patients with higher expression levels showed significantly inferior survival than those with lower expression levels. Enzyme-linked immunosorbent assay results of the expression levels of CD53 and CD47 from EVs in the bone marrow of patients with AML at diagnosis and at the time of complete remission with induction chemotherapy revealed that patients with downregulated CD53 and CD47 expression appeared to relapse less frequently. Network model analysis of EV proteins revealed several upregulated kinases, including LYN, CSNK2A1, SYK, CSK, and PTK2B. The potential cytotoxicity of several clinically applicable drugs that inhibit these kinases was tested in AML cell lines. The drugs lowered the viability of AML cells. The collective data suggest that AML-derived EVs could reflect essential leukemia biology.

scholarly journals Expression Levels of Human Equilibrative Nucleoside Transporter 1 and Deoxycytidine Kinase Enzyme as Prognostic Factors in Patients with Acute Myeloid Leukemia Treated with Cytarabine

Chemotherapy ◽  
2016 ◽  
Vol 61 (6) ◽  
pp. 313-318 ◽  
Author(s):  
Myrna Candelaria ◽  
Carmen Corrales-Alfaro ◽  
Olga Gutiérrez-Hernández ◽  
José Díaz-Chavez ◽  
Juan Labardini-Méndez ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cox Regression ◽  
Performance Status ◽  
Deoxycytidine Kinase ◽  
Nucleoside Transporter ◽  
Cox Regression Analysis ◽  
Expression Levels ◽  
Equilibrative Nucleoside Transporter ◽  
Acute Myeloid

Background: Cytarabine (Ara-C) is the primary drug in different treatment schemas for acute myeloid leukemia (AML) and requires the human equilibrative nucleoside transporter (hENT1) to enter cells. The deoxycytidine kinase (dCK) enzyme limits its activation rate. Therefore, decreased expression levels of these genes may influence the response rate to this drug. Methods: AML patients without previous treatment were enrolled. The expression of hENT1 and dCK genes was analyzed using RT-PCR. Clinical parameters were registered. All patients received Ara-C + doxorubicin as an induction regimen (7 + 3 schema). Descriptive statistics were used to analyze data. Uni- and multivariate analyses were performed to determine factors that influenced response and survival. Results: Twenty-eight patients were included from January 2011 until December 2012. Median age was 36.5 years. All patients had an adequate performance status (43% with ECOG 1 and 57% with ECOG 2). Cytogenetic risk was considered unfavorable in 54% of the patients. Complete response was achieved in 53.8%. Cox regression analysis showed that a higher hENT1 expression level was the only factor that influenced response and survival. Conclusions: These results highly suggest that the pharmacogenetic analyses of Ara-C influx may be decisive in AML patients.

Analysis of HOXA5 and HOXB3 Expression Complements Conventional Cytogenetic Analysis in Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2388-2388
Author(s):  
Damian P.J. Finnegan ◽  
Vivien M. Hodges ◽  
Alexander Thompson ◽  
Michael F. Quinn ◽  
Mervyn Humphries ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Expression Profiling ◽  
Cytogenetic Analysis ◽  
Myeloid Leukemia ◽  
Response To Treatment ◽  
Gene Rearrangements ◽  
Expression Levels ◽  
Conventional Cytogenetic Analysis ◽  
Favorable Group ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies with individual cases showing wide variations in response to treatment. Pre-treatment karyotype analysis may be used to stratify cases into one of three prognostic classes: favorable, intermediate or adverse. Favorable karyotypes, t(15;17), t(8;21) and inv(16), are associated with the presence PML-RARα, AML1-ETO and CBFβ-MYH11 gene rearrangements respectively. The adverse cytogenetic abnormalities are monosomy 5, monosomy 7, deletion of chromosome 5q, abnormalities of chromosome 3q and a complex karyotype. All remaining abnormalities are associated with an intermediate prognosis. Approximately 5–10% of cases cannot be stratified due to failure of cytogenetic analysis. Cryptic gene rearrangements, which cannot be detected by karyotyping, may lead to assignment of cases to incorrect prognostic classes. These problems may result in sub-optimal or over-treatment of patients. Using an artificial neural network-based analysis of HOX gene expression profiles generated by real-time quantitative PCR (RT-QPCR) we have previously shown that the favorable and intermediate cytogenetic classes are characterised by low HOXA5 (Ct value > 29.5) and high HOXB3 (Ct value < 25) expression respectively (Blood2006; 108: Abstract 2318). We have now measured HOXA5 and HOXB3 expression levels by RT-QPCR in a fresh set of 78 newly diagnosed cases of AML (31 favorable, 38 intermediate and 9 adverse karyotypes as determined by conventional cytogenetic analysis). All 31 cases with favorable cytogenetics had HOXA5 Ct values > 29.5 with twenty-nine (93.5%) having Ct values > 33. Therefore, using a HOXA5 Ct ≥; 33 to define membership of the favorable prognostic class and HOXA5 Ct < 33 to define membership of a non-favorable class, 72 cases (92.3%) were correctly assigned (29 favorable and 43 non-favorable). Of the 4 cases with non-favorable cytogenetics, originally misclassified by HOXA5 expression profiling, two were subsequently found to have cryptic rearrangements of PML-RARα and therefore should have been included within the favorable group. This increased the percentage of cases correctly assigned by HOXA5 expression profiling alone to 94.9%. We also found that within the favorable group, AML with t(15;17) or t(8;21) was characterized by low expression of HOXB3 (Ct range 30.9 to 37.4, median Ct 34.1) whereas AML with inv(16) had a distinct signature characterized by higher HOXB3 expression (Ct range 26.4 to 30.1, median Ct 28.0). In addition, we have identified a subset of patients with intermediate cytogenetics who have high white cell counts, low HOXB3 expression and an inferior response to treatment. Therefore, in AML, the measurement of expression levels of only two HOX genes, HOXA5 and HOXB3 , complements cytogenetic analysis and may improve the yield of favorable gene rearrangements detected and provide additional prognostic information for cases with intermediate or failed cytogenetics.

Incidence and Clinical Impact of TET2 Mutations in Acute Myeloid Leukemia Patients Treated within the EORTC/GIMEMA AML-12/06991 AML Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2609-2609
Author(s):  
M. G Aslanyan ◽  
S. M.C. Langemeijer ◽  
D. Cilloni ◽  
G. Saglio ◽  
JP Marie ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Regulation Of Gene Expression ◽  
Premature Stop Codon ◽  
Clinical Impact ◽  
Mrna Levels ◽  
Expression Levels ◽  
Therapeutic Decisions ◽  
Acute Myeloid

Abstract Abstract 2609 Poster Board II-585 Defining specific subgroups within AML based on cytogenetic and molecular markers is crucial for diagnostic and prognostic purposes, as well as for adequate therapeutic decisions. Recently, we and others have reported mutations in a novel gene, TET2, that occur in a broad spectrum of myeloid neoplasms. Recent publications regarding the function of the TET protein family members implicate that these proteins play a role in epigenetic regulation of gene expression through DNA methylation, a process known to be disturbed in several hematological malignancies. Thus far, TET2 represents the most frequently mutated gene in myelodysplastic syndromes (26%), and mutations are also frequent in myeloproliferative disorders (12%), mastocytosis (30%), acute myeloid leukemia (10%) and chronic myelomonocytic leukemia (22%). The aim of this study was to define the incidence and clinical impact of TET2 mutations in acute myeloid leukemia patients who were treated uniformously within a defined clinical trial. In addition, we measured the mRNA levels of TET2 in patients with and without TET2 mutations, in order to establish whether the TET2 expression levels might correlate with clinical outcome. We performed direct DNA and/or RNA sequencing of the TET2 gene for mutation analysis and Q-PCR to measure mRNA expression levels. A cohort of up to 400 AML patients that was treated within the EORTC/GIMEMA AML-12/06991 trial was screened. In this trial newly diagnosed patients with AML between 15 and 60 years of age were included, with the exception of patients with acute promyelocytic leukemia. TET2 mutations were detected in 9% of the cases. Mutations were scattered along the whole coding region of the TET2 gene. In 12% of the cases, this led to a premature stop codon, in 24% to a frameshift and premature truncation of the reading frame, and in 60% to missense substitutions, clustering within the two conserved box 1 and box 2 regions of the TET2 gene. In one patient, a splice site mutation was found. TET2 mutations often co-occurred with other well-known mutations, including mutations in the nucleophosmin gene (NPM1), mutations of the fms-like tyrosine kinase 3 (FLT3), and the mixed lineage leukemia gene (MLL). Truncations in the TET2 gene co-occurred most frequently with mutations of NPM1 and FLT3. To determine the clinical significance of TET2 mutations, overall survival of TET2 mutated versus TET2 wild type patients was assessed. Analysis based on the first 224 AML patients showed a clear trend towards poor prognosis of patients carrying a TET2 mutation (p=0.065). So far, TET2 expression levels do not seem to correlate with clinical outcome. The multivariate analysis of the whole cohort will be presented. We conclude that TET2 represents a novel genetic marker that is mutated in approximately 10% of the cases of de novo AML and that in this patient category, mutation of TET2 correlates with poor clinical outcome. Disclosures: Muus: Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Molecular Mechanism Of Regulation Of Extramedullary Infiltration In AML1/ETO Positive Acute Myeloid Leukemia By APP/ERK/MMP-2

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3769-3769
Author(s):  
Guopan Yu ◽  
Fan Yi Meng ◽  
Ling Jiang ◽  
Changxin Yin ◽  
Zhixiang Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Molecular Mechanism ◽  
Myeloid Leukemia ◽  
High Expression ◽  
Control Group ◽  
Expression Levels ◽  
High Expression Group ◽  
App Gene ◽  
Acute Myeloid

Abstract Amyloid precursor protein (APP) has been reported to be highly expressed in AML1/ETO positive acute myeloid leukemia (AML1/ETO+ AML), and we found it express even higher in those with extramedullary infiltration in our previous study. But it’s still unknown what role APP plays and how it works in AML1/ETO+ AML. This study was designed to investigate the effect of APP gene on the prognosis and its molecular mechanism of extramedullary infiltration in the patients with AML1/ETO+ AML. 44 cases of AML1/ETO+ AML patients with median age of 29 years old, who were admitted to our hospital from February, 2006 to February, 2012 and made the diagnosis according to WHO2008 diagnosis standard, and had completed conventional induction, consolidation and intensive therapy, were investigated in this study. They were divided into high expression group (n=22) and low one (n=22) according to APP mRNA median expression level from bone marrow cells before the first chemotherapy by QRT-PCR. Some of bone marrow samples were checked by Western Blot, and 5 biopsy specimens from extramedullary infiltration were tested by APP antibody immunohistochemistry staining. Incidence of extramedullary leukemia (EML), complete response (CR), overall survival (OS), and recurrence free survival (RFS) was differentiated between the two groups. Differences of cell ultrastructure, migration, proliferation, apoptosis and expression of ERK, MMP-2, MMP-9 and CXCR4 were studied on Kasumi-1 cell line between wild, negative control (NC) and si-APP group in which the expression levels of APP gene were down regulated with application of siRNA technology.Çå The incidence of EML was significantly different (45.5% versus 9.1%) in the two groups (P=0.007) and it was positively correlative with the expression levels of APP mRNA (rp=0.435, P=0.004). Extramedullary infiltration site also showed high expression of APP by immunohistochemistry, while the control group was negative. Not only CR rate after two courses of chemotherapy, but also OS and RFS with median follow-up of 28(4-70) months, of high expression group was all significantly lower than that of low expression group (Table 1). Compared with the wild and NC group, cell apoptosis of si-APP group was significantly increased (12.33 ± 0.75 vs 19.80 ± 1.51, P=0.000); the number of microvilli on the surface of the cell membrane significantly reduced; the ability of the cell migration by Tanswell chamber migration assay significantly decreased (P=0.004); and expression of P-ERK, c-MYC, MMP-2 decreased significantly which was confirmed by ERK and c-MYC blocker treatment (Figure 1). In sum, incidence of EML is significantly higher and the prognosis is poor in the patients with AML1/ETO+ AML with high expression of APP gene. We first describe that APP gene may mediate AML1/ETO+ leukemia cells in the development of extramedullary infiltration by up-regulation of the ERK/MMP-2 pathway. Disclosures: No relevant conflicts of interest to declare.

Expression Profiling Of Selected Polycomb Complex Genes In Childhood Acute Myeloid Leukemia Revealed An Overexpression Of EZH2 In Acute Promyelocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4895-4895
Author(s):  
Amanda Faria Figueiredo ◽  
Renata Binato ◽  
Andre Mencalha ◽  
Roberto Capela Matos ◽  
Raul C Ribeiro ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Platelet Count ◽  
Children And Adolescents ◽  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
Promyelocytic Leukemia ◽  
Mrna Levels ◽  
Expression Levels ◽  
Ezh2 Expression ◽  
Acute Myeloid

Abstract Acute promyelocytic leukemia (APL) in children and adolescents accounts for about 20% of cases of acute myeloid leukemia (AML) in Brazil. The reasons for the relatively high incidence of APL among children and adolescents in Brazil and other Latin countries remain elusive. Epigenetic constitutional and/or environmental factors might be implicated in the mechanism of APL. The Polycomb group (PcG) genes are critical for differentiation and cell-cycle regulation and maintenance of epigenetic memory of living organisms. Aberrant expression of PcG genes has been observed in human tumors, including AML. In this study, we sought to determine the expression levels of 4 genes from the PcG repressive complexes EZH2, YY1, BMI1 and SUZ12 in acohort of 52 children with AML or APL (male, 32; female, 20; median age 7.8 years, range 4 months-18 years). Cells from healthy children (male, 2; female, 2; median age, 10.7 years, range 6-15 years) were used as the control group. Quantitative determination of mRNA levels was performed using Power SYBR Green PCR Master Mix® (Applied Biosystems, Foster City, CA, USA) in a Rotor Gene® thermocycler (QIAGEN). Expression levels were estimated in triplicate, and ß-actin was used as an internal control. All statistical analyses were performed using the GraphPad Prim 5.0 System. Multiple pairwise comparisons were made using a one-way analysis of variance (ANOVA) test; P<0.05 was considered statistically significant. Despite showing broad variation among patients and controls, the expression levels of YY1 (controls, 1.16 ±SE 0.73; M1/M2, 0.63±1.07; M4/M5 0.217±0.71; APL, 0.62±3.24; p=0.19); SUZ12 (control, 1.11 ±0.93; M1/M2, 0.12±1.65; APL 2.4±3.42; M4/M5, 0.34 ± 10.30; p=0.18), and BMI1 (control, 0.041 ± 0.77; M1/M2: 0.043 ±0.10; M4/M5, 0.016± 0.23; APL, 0.12 ± 0.59; p=0.37)did not differsignificantly between controls and patients grouped according to the major AML subtypes (M1/M2, 15 cases, median age 10.8 years, range 4-18 years; M4/M5, 21 cases,median 4.5 years, range 5 months-18 years; APL 16 cases, median 9.8 years, range, 1-17 years). However, the EZH2 expression levels (control, 0.0008818±0.03675; M1/M2, 0.001495±0.03296; M4/M5 0.008215±0.09313; APL, 0.07180± 0.3402; p=0.0092) were significantly higher in APL. Among patients with APL, the expression levels of EZH2 did not differ significantly according to age (EZH2 expression, 0.23±0.44, age 0-8 years; 0.05±0.46, age 9-18 years; p=0.112), white blood cell count (EZH2 expression 0.07±0.65, WBC < 10 x 109/L; 0.10±0.38, WBC ≥ 10 x 109/L; p=0.148) or platelet count (EZH2 expression 0.20±0.49, platelet count < 40 x109/L; 0.06 ±0.04, platelet count ≥ 40 x 109/L; p=0.13). Several studies have shown that EZH2 is deregulated in several human cancers. Here we extend this data by informing that EZH2 is highly overexpressed in pediatric APL. APL in children less than 8 years of age tends to be associated with higher EZH2 gene expression levels, suggesting that constitutional epigenetic factors may play a driver role in pediatric APL leukemogenesis. Disclosures: No relevant conflicts of interest to declare.

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