C-Myc facilitates prediction of "7+3" induction failure in de novo acute myeloid leukaemia with high-risk cytogenetics
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ABSTRACT:
PROVIDER: PRJNA692419 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13443200_1.fastq.gz | Fastqsanger.gz | |||
| SRR13443200_2.fastq.gz | Fastqsanger.gz | |||
| SRR13443201_1.fastq.gz | Fastqsanger.gz | |||
| SRR13443201_2.fastq.gz | Fastqsanger.gz | |||
| SRR13443202_1.fastq.gz | Fastqsanger.gz |
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Project description:This study aimed to identify whether c-Myc could facilitate prediction of "7+3" induction failure in de novo acute myeloid leukaemia (AML) with high-risk cytogenetics. Seventy-five untreated de novo AML patients who completed the "7+3" induction therapy were enrolled (24 patients from a prospective cohort; 51 patients from a retrospective cohort) and stratified into complete remission (CR) and non-CR groups. Myc-associated molecular signature between the CR and non-CR groups in the prospective cohort was compared after gene set enrichment analysis. c-Myc protein expression was assessed via immunohistochemical staining. A high c-Myc-immunopositivity was defined when ≥ 40% of bone marrow myeloblasts were c-Myc (+). Our results revealed that AML patients who did not achieve CR by the "7+3" induction therapy had a higher Myc gene expression than those that achieved CR (p=0.047). Myc gene expression was positively correlated with c-Myc protein expression (p=0.014). Although the non-CR group did not have more c-Myc protein expression compared to that in the CR group (p=0.151), combination of high c-Myc-immunopositivity and high-risk cytogenetics increased the probability of "7+3" induction failure compared to that in high-risk cytogenetics alone. Induction strategies other than “7+3” might be a solution for de novo patients with high c-Myc-immunopositivity and high-risk cytogenetics.
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Project description:This study explored resistance functions and their interactions in de novo AML treated with the "7 + 3" induction regimen. We analyzed RNA-sequencing profiles of whole bone marrow samples from 52 de novo AML patients who completed the "7 + 3" regimen and stratified patients into CR (n = 35) and non-CR (n = 17) groups. A systematic gene set analysis revealed significant associations between chemoresistance and mTOR (P < .001), myc (P < .001), mitochondrial oxidative phosphorylation (P < .001), and stemness (P = .002). These functions were independent with regard to gene contents and activity scores. An integration of these four functions showed a prediction of chemoresistance (area under the receiver operating characteristic curve = 0.815) superior to that of each function alone. Moreover, our proposed seven-gene scoring system significantly correlated with the four-function model (r = .97; P < .001) to predict chemoresistance to the "7 + 3" regimen. On multivariate analysis, a seven-gene score of ≥-0.027 (hazard ratio: 11.18; 95% confidence interval: 2.06-60.65; P = .005) was an independent risk factor for induction failure. In summary, Myc, OXPHOS, mTOR, and stemness were responsive for chemoresistance in AML. Treatments other than the "7 + 3" regimen need to be considered for de novo AML patients predicted to be refractory to the "7 + 3" regimen.
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Project description:The clinical and cytogenetic features associated with T-cell acute lymphoblastic leukemia (T-ALL) are not predictive of early treatment failure. Based on the hypothesis that microarrays might identify patients who fail therapy, we used the Affymetrix U133 Plus 2.0 chip and prediction analysis of microarrays (PAM) to profile 50 newly diagnosed patients who were treated in the Children's Oncology Group (COG) T-ALL Study 9404. We identified a 116-member genomic classifier that could accurately distinguish all 6 induction failure (IF) cases from 44 patients who achieved remission; network analyses suggest a prominent role for genes mediating cellular quiescence. Seven genes were similarly upregulated in both the genomic classifier for IF patients and T-ALL cell lines having acquired resistance to neoplastic agents, identifying potential target genes for further study in drug resistance. We tested whether our classifier could predict IF within 42 patient samples obtained from COG 8704 and, using PAM to define a smaller classifier for the U133A chip, correctly identified the single IF case and patients with persistently circulating blasts. Genetic profiling may identify T-ALL patients who are likely to fail induction and for whom alternate treatment strategies might be beneficial. This SuperSeries is composed of the SubSeries listed below.
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Project description:BackgroundHeart failure is one of the most common diseases of adults in Europe, with an overall prevalence of 1-2%. Among persons aged 60 and above, its prevalence is above 10% in men and 8% in women. Acute heart failure has a poor prognosis; it is associated with a high rate of rehospitalization and a 1-year mortality of 20-30%.MethodsThis review is based on pertinent literature, including guidelines, retrieved by a selective search in PubMed.ResultsThere are different types of acute heart failure; the basic diagnostic assessment is performed at once and consists of ECG, echocardiography, and the measurement of N-terminal pro-brain natriuretic peptide (NTproBNP) and troponin levels. The most common causes of decompensation are arrhythmia, valvular dysfunction, and acute cardiac ischemia, each of which accounts for 30% of cases. The potential indication for immediate revascularization should be carefully considered in cases where acute heart failure is due to coronary heart disease. The basic treatment of acute heart failure is symptomatic, with the administration of oxygen, diuretics, and vasodilators. Ino-tropic agents, vasopressors, and temporary mechanical support for the circulatory system are only used to treat cardiogenic shock.ConclusionThe treatment of acute heart failure is markedly less evidence-based than that of chronic heart failure. Newer treatment approaches that are intended to improve outcomes still need to be tested in multicenter trials.
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Project description:The CD4+Foxp3+ regulatory T cells play an essential role in maintaining tolerance via their suppressive function on conventional T cells. The intracellular signaling pathways that regulate Foxp3 expression are largely unknown. In this study we describe a novel inhibitory role for AKT in regulating de novo induction of Foxp3 both in vivo and in vitro. A constitutively active allele of AKT significantly diminished TGF-â induced Foxp3 induction via a rapamycin-sensitive pathway, establishing a role for the AKT-mTOR axis in Treg cells. Moreover, the observed impairment in Foxp3 induction was paralleled by a selective downmodulation of the imparted Treg transcriptional signature highlighting the importance of the balance of intracellular signals in Treg differentiation . Our results provide a basis for further elucidation of molecular mechanisms that regulate Foxp3 induction and identify AKT as an important negative regulator of this process. Keywords: Cell population comparison
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Project description:The clinical and cytogenetic features associated with T-cell acute lymphoblastic leukemia (T-ALL) are not predictive of early treatment failure. Based on the hypothesis that microarrays might identify patients who fail therapy, we used the Affymetrix U133 Plus 2.0 chip and prediction analysis of microarrays (PAM) to profile 50 newly diagnosed patients who were treated in the Children's Oncology Group (COG) T-ALL Study 9404. We identified a 116-member genomic classifier that could accurately distinguish all 6 induction failure (IF) cases from 44 patients who achieved remission; network analyses suggest a prominent role for genes mediating cellular quiescence. Seven genes were similarly upregulated in both the genomic classifier for IF patients and T-ALL cell lines having acquired resistance to neoplastic agents, identifying potential target genes for further study in drug resistance. We tested whether our classifier could predict IF within 42 patient samples obtained from COG 8704 and, using PAM to define a smaller classifier for the U133A chip, correctly identified the single IF case and patients with persistently circulating blasts. Genetic profiling may identify T-ALL patients who are likely to fail induction and for whom alternate treatment strategies might be beneficial.
2009-01-29 | GSE14615 | GEO