This SuperSeries is composed of the SubSeries listed below.
LncRNA Expression Discriminates Karyotype and Predicts Survival in B-Lymphoblastic Leukemia.
Specimen part, Disease, Treatment
View SamplesLong non-coding RNAs (lncRNAs) have been found to play a role in gene regulation with dysregulated expression in various cancers. The precise role that lncRNA expression plays in the pathogenesis of B-acute lymphoblastic leukemia (B-ALL) is unknown. Therefore, unbiased microarray profiling was performed on human B-ALL specimens and it was determined that lncRNA expression correlates with cytogenetic abnormalities, which was confirmed by RT-qPCR in a large set of B-ALL cases. Importantly, high expression of BALR-2 correlated with poor overall survival and diminished response to prednisone treatment. In line with a function for this lncRNA in regulating cell survival, BALR-2 knockdown led to reduced proliferation, increased apoptosis, and increased sensitivity to prednisolone treatment. Conversely, overexpression of BALR-2 led to increased cell growth and resistance to prednisone treatment. Interestingly, BALR-2 expression was repressed by prednisolone treatment and its knockdown led to upregulation of the glucocorticoid response pathway in both human and mouse B-cells. Together, these findings indicate that BALR-2 plays a functional role in the pathogenesis and/or clinical responsiveness of B-ALL and that altering the levels of particular lncRNAs may provide a future direction for therapeutic development.
LncRNA Expression Discriminates Karyotype and Predicts Survival in B-Lymphoblastic Leukemia.
Specimen part, Treatment
View SamplesWe examined if pediatric AMLs rank-ordered according to C/EBP expression showed the activation of similar pathways. AML samples were dichotomized into groups including the upper quartile (Q1) and the lower three quartiles (Q2-4) according to their C/EBP expression values. Moreover, AML samples were associated to French-American-British (FAB) classification.
CREB engages C/EBPδ to initiate leukemogenesis.
Specimen part, Disease
View SamplesTo examine the role of CREB overexpression in hematopoiesis, we created a model of leukemia in zebrafish by overexpressing the human CREB in the myeloid hematopoietic lineage. Whole transcriptome analysis of kidney-marrow revealed 171 genes differently expressed between CREB- and control-zebrafish (five per group). Interestingly, the integration of this signature with human deposited data revealed that this tumor resembled a human AML at transcriptome level.
CREB engages C/EBPδ to initiate leukemogenesis.
Specimen part
View SamplesIncreased CREB levels and upregulation of its target genes expression resulted in increased myelopoiesis and colony formation.
MicroRNA-34b promoter hypermethylation induces CREB overexpression and contributes to myeloid transformation.
Specimen part, Disease, Disease stage, Subject
View SamplesZNF521 is a multiple zinc finger transcription factor previously identified because abundantly and selectively expressed in normal CD34+ hematopoietic stem and progenitor cells. From microarray datasets, aberrant expression of ZNF521 has been reported in both pediatric and adult acute myeloid leukemia (AML) patients with MLL gene rearrangements. However, a proper validation of microarray data is lacking, likewise ZNF521 contribution in MLL-rearranged AML is still uncertain. In this study, we show that ZNF521 is significantly upregulated in MLL translocated AML patients from a large pediatric cohort, regardless of the type of MLL translocations such as MLL-AF9, MLL-ENL, MLL-AF10 and MLL-AF6 fusion genes. Our in vitro functional studies demonstrate that ZNF521 play a critical role in the maintenance of the undifferentiated state of MLL-rearranged cells. Furthermore, analysis of the ZNF521 gene promoter region shows that ZNF521 is a direct downstream target of both MLL-AF9 and MLL-ENL fusion proteins. Gene expression profiling of MLL-AF9-rearranged THP-1 cells after depletion of ZNF521 reveals correlation with several expression signatures including stem cell-like and MLL fusion dependent programs. These data suggest that MLL fusion proteins activate ZNF521 expression to maintain the undifferentiated state and contribute to leukemogenesis.
ZNF521 sustains the differentiation block in MLL-rearranged acute myeloid leukemia.
Specimen part, Cell line
View SamplesWe retrospectively analyzed AML patients enrolled in the AIEOP since 2000, 42 patients with 11q23 rearrangement were analyzed by gene expression profile
MLL partner genes drive distinct gene expression profiles and genomic alterations in pediatric acute myeloid leukemia: an AIEOP study.
Disease, Disease stage
View SamplesWe examined if the minimal residual disease (MRD) and the Allelic Ratio (AR) of FLT3 internal tandem duplication (ITD) mutated patients may be prognostic factors. We correlated these parameters both with event free survival (EFS), with incidence of relapse and with gene expression profile (GEP). GEP showed that patients with high-ITD-AR or persistent MRD had different expression profiles. Results indicated that the ITD-AR levels and the MRD after I induction course are associated with transcriptional oncogenic profiles, which highlight differences in epigenetic control that may explain the variability in outcome among FLT3-ITD patients
Characterization of children with FLT3-ITD acute myeloid leukemia: a report from the AIEOP AML-2002 study group.
Specimen part, Disease
View SamplesWe set out to investigate whether a histone deacetylase inhibitor (HDACi) would be effective in an in vitro model for the neurodegenerative disease Friedreich ataxia (FRDA) and to evaluate safety and surrogate markers of efficacy in a phase I clinical trial in patients. In the neuronal cell model, HDACi 109/RG2833 increases FXN mRNA levels and frataxin protein, with concomitant changes in the epigenetic state of the gene. Chromatin signatures indicate that histone H3 lysine 9 is a key residue for gene silencing through methylation and reactivation through acetylation, mediated by the HDACi. Drug treatment in FRDA patients demonstrated increased FXN mRNA and H3 lysine 9 acetylation in peripheral blood mononuclear cells. No safety issues were encountered.
Epigenetic therapy for Friedreich ataxia.
Time
View SamplesActivity-dependent transcriptional profiling was performed in the basolateral amygdala in order to identify unique genetic markers for functionally distinct neuronal populations
Antagonistic negative and positive neurons of the basolateral amygdala.
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