ATP-binding casette transporter expression in acute myeloid leukemia: association within vitrocytotoxicity and prognostic markers

2017 ◽  
Vol 18 (3) ◽  
pp. 235-244 ◽  
Author(s):  
Savitha Varatharajan ◽  
Ajay Abraham ◽  
Sreeja Karathedath ◽  
Sukanya Ganesan ◽  
Kavitha M Lakshmi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Markers ◽  
Atp Binding ◽  
Transporter Expression ◽  
Acute Myeloid

scholarly journals Expression of some ATP-binding cassette transporters in acute myeloid leukemia

2017 ◽  
Vol 9 (4) ◽  
Author(s):  
Antonella Maria Salvia ◽  
Flavia Cuviello ◽  
Sabrina Coluzzi ◽  
Roberta Nuccorini ◽  
Immacolata Attolico ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Abc Transporters ◽  
Healthy Subjects ◽  
Myeloid Leukemia ◽  
Resistance Mechanisms ◽  
Atp Binding ◽  
Atp Binding Cassette Transporters ◽  
Acute Myeloid ◽  
Atp Binding Cassette

Hematopoietic cells express ATP binding cassette (ABC) transporters in relation to different degrees of differentiation. One of the known multidrug resistance mechanisms in acute myeloid leukemia (AML) is the overexpression of efflux pumps belonging to the superfamily of ABC transporters such as ABCB1, ABCG2 and ABCC1. Although several studies were carried out to correlate ABC transporters expression with drug resistance, little is known about their role as markers of diagnosis and progression of the disease. For this purpose we investigated the expression, by real-time PCR, of some ABC genes in bone marrow samples of AML patients at diagnosis and after induction therapy. At diagnosis, ABCG2 was always down-regulated, while an up regulated trend for ABCC1 was observed. After therapy the examined genes showed a different expression trend and approached the values of healthy subjects suggesting that this event could be considered as a marker of AML regression. The expression levels of some ABC transporters such as ABCC6, seems to be related to gender, age and to the presence of FLT3/ITD gene mutation.

RNA-Sequencing Unveils Cryptic Fusions in Patients with Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1278-1278
Author(s):  
Fabiana Ostronoff ◽  
Matthew Fitzgibbon ◽  
Martin McIntosh ◽  
Rhonda E. Ries ◽  
Alan S. Gamis ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Rna Sequencing ◽  
Myeloid Leukemia ◽  
Prognostic Markers ◽  
Normal Karyotype ◽  
Fusion Transcript ◽  
Rna Seq ◽  
Illumina Hiseq ◽  
Normal Controls ◽  
Acute Myeloid

Abstract Abstract 1278 Introduction: Acute myeloid leukemia (AML) represents a heterogeneous group of malignancies with great variability in response to therapy. In recent years, an increasing list of molecular markers with prognostic significance in AML has been identified; nonetheless, new prognostic markers and therapeutic targets are still needed. The aim of this study was to identify and verify fusion transcripts using RNA-Sequencing (RNA-Seq) that would be otherwise undetectable by conventional karyotyping. Methods: Transcriptome Sequence data is generated by high-throughput short-read RNA-Seq performed for each AML sample on the Illumina HiSeq. Poly(A) RNA is captured with poly(T) magnetic beads, fragmented, copied to cDNA libraries with reverse transcriptase and random primers. Each library is subjected to 50-cycle paired-end sequencing on the Illumina HiSeq at Hudson Alpha. Filtered Fastq files are processed with TopHat-Fusion [Kim2011,Trapnell2009] alignment software to discover cryptic fusions in RNA-Seq data without relying on known, annotated models. This process yielded an average of 20 million alignable reads per sample. Cord blood blast cell transcripts are also processed and serve as normal controls. A series of filtering steps eliminate junctions commonly found to be in error. Filtered junctions found in at least 3 AML samples and no normal controls are retained as AML-associated candidate junctions. Visual curation of candidates is performed using Integrative Genomics Viewer. Candidate fusions were verified by RT-PCR amplification of the AML-associated fusions in the index cases. Fusion transcript product, as well as the break point junction was verified by Sanger sequencing Results: Diagnostic specimens from 70 patients with de novo AML that included patients with normal karyotype (NK, N=31), core-binding factor (CBF) AML (N=33) and other (N=6) were sequenced. Age at diagnosis varied from 10 months to 69 years (Median 12 years). White blood cell count (WBC) and blast percentage were 49×109/L (range, 2.4 to 496×109/L) and 78% (40% to 100%), respectively. Bioinformatic evaluation of the RNA-Seq data revealed 67 high-value novel fusions that were not detected by conventional karyotyping: 54 (80.6%) were intra- and 13 (19.4%) inter-chromosomal junctions. The number of novel translocations varied in different cytogenetic groups, with 22 novel fusions detected in those with NK (16 intra and 6 inter-chromosomal junctions), 37 CBF (32 intra and 5 inter-chromosomal junctions) and 8 in “other” (6 intra and 2 inter-chromosomal junctions). Thirteen novel fusions (19.4%) were found in at least 2 or more screened-patients: two (15.4%) inter- and 11 (84.6%) intra-chromosomal junctions. Median number of fusions identified per patient was 2 (range, 1 to 6). Novel fusions involving PDGFR-β gene were identified in two patients, each with a different translocation partner (G3BP1 and ETV6, which was an intra and inter-chromosomal fusions, respectively). Sequencing of the fusion transcript junctions verified the fusion junctions and demonstrated in frame fusions of G3BP1 and ETV6 to the kinase domain coding region of PDGFR-β, identical junction to that seen in cases of imatinib sensitive idiopathic hypereosinophilic syndrome (IHES). Frequency validation in 100 adult and 100 pediatric cases identified one additional patient with G3BP1-PDGFR-β. Cryptic NUP98/NSD1 was identified and verified in two patients with normal karyotype as well as NUP98/HOXD13 translocation in one patient. Frequency determination of NUP98/NSD1 demonstrated prevalence of 7.8% in patients with NK, and that of 13% in patients with FLT3/ITD. Patients who harbored both NUP98/NSD1 fusion and FLT3/ITD had a dismal remission induction rate (CR rate in FLT3/ITD with and without NUP98/NSD1 was 28% vs. 73%; p=0.002). Conclusion: Our data show the applicability of RNA-Seq as a tool to discover cryptic fusion transcripts in AML. These novel fusions may define new independent prognostic markers and potential therapeutic targets for patients with this highly treatment-resistant disease. Disclosures: No relevant conflicts of interest to declare.

Overall Hydroxymethylation Levels As an Independent Prognostic Marker in Intermediate-Cytogenetic Risk Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1375-1375
Author(s):  
Marina Díaz-Beyá ◽  
Alfons Navarro ◽  
Rut Tejero ◽  
Marta Pratcorona ◽  
Tania Díaz ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Prognostic Markers ◽  
Response Rate ◽  
Wild Type ◽  
Mirna Signature ◽  
Worse Prognosis ◽  
Acute Myeloid

Abstract Abstract 1375 Introduction: Acute myeloid leukemia (AML) is a highly heterogeneous disease, with diverse genetic and epigenetic variables determining sensitivity to current standard therapy. A disruption of the normal DNA methylation pattern, which can result in altered gene and microRNA (miRNAs) expression, has been observed in different AML subtypes. Hydroxymethylation of 5-methylcytosine (5-mC) has recently been described as an intermediate key step in the process of DNA demethylation. Nonetheless, the correlation of DNA methylation and hydroxymethylation levels with clinical and biological characteristics and clinical outcome in AML is mostly unknown. Aim: To investigate the prognostic impact of overall methylation and hydroxymethylation levels in patients with intermediate-cytogenetic risk AML (IR-AML) and to identify miRNAs correlated with methylation and hydroxymethylation in these patients. Patients and Methods: We have analyzed 86 IR-AML patients (median age, 53 [range, 17–74]; 52% males) who received intensive therapy from 1994 to 2009 in a single institution. The level of overall methylation and hydroxymethylation in total DNA was estimated after determining the percentage of 5-mC and hydroxymethylcytosine (5-hmC), using anti-5-mC and anti-5-hmC monoclonal antibodies (MethylFlash Methylated or Hydroxymethylated DNA Quantification Kit, Epigentek). The expression of 670 mature miRNAs was analyzed using TaqMan Human MicroRNA Arrays (Applied Biosystems). The statistical analysis was performed with SPSS version 15.0.1 and R software version 2.9.0. MaxStat package of R was used to determine the optimal cutoffs. Results: The univariate analysis for overall methylation showed that patients with lower levels of methylation (cutoff < percentile 75) had shorter overall survival (OS) than those with higher 5-mC levels (5-year OS: 30±6% vs 52±11%; p=0.03) and a trend for shorter leukemia-free survival (LFS)(p=0.06). Overall methylation levels did not show any correlation with clinical features at diagnosis or with gene mutations, including DNMT3A. Concerning hydroxymethylation, patients with lower 5-hmC levels had a worse prognosis than those with higher 5-hmC levels, with a lower complete response rate (79% vs. 96%; p=0.04), shorter OS (5-yr OS: 21± 6% vs. 55± 6%; p=0.008), and shorter LFS (5-yr LFS: 24±8% vs. 52 ±10%; p=0.03). Interestingly, when analyzed as a continuous variable, 5-hmC levels retained their prognostic value as a marker of response rate (T-test, p=0.007), OS (Cox, p=0.015), and LFS (Cox, p=0.041). Moreover, 5-hmC levels were inversely correlated with FLT3-ITD (p=0.001) and the FLT3-ITD/FLT3wild-type ratio (Pearson correlation:-0.6; p=0.01). The multivariate analyses, including the main clinical and biological variables, identified older age, wild-type NPM1, FLT3-ITD, and lower 5-hmC levels (HR=3.072; 95% CI: 1.096–3.917; p=0.025) as independent prognostic markers of shorter OS and wild-type NPM1, FLT3-ITD, and lower 5-hmC levels (HR=2.002, 95% CI: 1.032–3.881, p=0.040) as independent prognostic markers of shorter LFS. Of note, lower 5-hmC levels retained their value as a marker of worse prognosis in the subgroup of IR-AML patients with unfavorable molecular markers (wild-type NPM1 and CEBPA and/or FLT3-ITD; p= 0.037). Finally, we have identified a 3-miRNA signature (miR-378*, p=0.02; miR-493, p=0.02; and miR-181, p=0.02) associated with global methylation levels, and a 12-miRNA signature associated with hydroxymethylation, including miR-183* (p=0.001), miR-125a-3p (p= 0.01), miR-586 (p=0.02), and miR-513–3p (p=0.02). Conclusions: Hydroxymethylation levels appear as an independent prognostic factor in IR-AML and maintain their prognostic value in the subset of patients with unfavorable molecular markers. Moreover, methylation and hydroxymethylation are associated with specific miRNA profiles. Further studies are warranted to confirm the clinical impact of these findings and to clarify the underlying molecular mechanisms. Disclosures: No relevant conflicts of interest to declare.

ATP-binding cassette (ABC) proteins in untreated acute myeloid leukemia (AML) in patients 60 years and older (CALGB 9760)

2005 ◽  
Vol 23 (16_suppl) ◽  
pp. 6551-6551
Author(s):  
M. R. Baer ◽  
J. S. Shoemaker ◽  
R. Barrier ◽  
N. W. Cuviello ◽  
K. L. O’Loughlin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Atp Binding ◽  
Abc Proteins ◽  
Acute Myeloid ◽  
Atp Binding Cassette

scholarly journals The Study of SALL4 Gene and BMI-1 Gene Expression in Acute Myeloid Leukemia Patients

2019 ◽  
Vol 51 (3) ◽  
pp. 265-270
Author(s):  
Rania Shafik Swelem ◽  
Dalia Abdelmoety Elneely ◽  
Ahmed Abdel Rahman Shehata
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Markers ◽  
Strong Association ◽  
Leukemia Cell ◽  
Human Leukemia ◽  
Hematopoietic Stem ◽  
Leukemia Cell Lines ◽  
Polymerase Chain ◽  
Acute Myeloid

Abstract Background In acute myeloid leukemia (AML), many genes have been studied as prognostic markers. SALL4 is expressed constitutively in human leukemia cell lines and primary AML cells. BMI-1 is expressed highly in purified hematopoietic stem cells (HSCs), and its expression declines with differentiation. Objective To study the expression levels of SALL4 and BMI-1 and their clinical significance in patients with AML. Methods The study was performed with 60 patients newly diagnosed with AML and 50 control individuals. SALL4 and BMI-1 expression detection were performed using real-time polymerase chain reaction (PCR). Results The expression of SALL4 and BMI-1 was significantly higher in cases of AML and showed a strong association with failure to achieve complete remission (CR) or with relapse (P = .02, P = .03, respectively). In multivariate analysis, these genes were the most powerful independent predictors of poor prognosis (P = .01 for SALL4, P = .02 for BMI-1). Conclusion SALL4 and BMI-1 are significant prognostic factors in AML and could be strong targets for novel types of therapy.

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