Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA284119 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2028010.fastq.gz | Fastqsanger.gz | |||
| SRR2028011.fastq.gz | Fastqsanger.gz | |||
| SRR2028012.fastq.gz | Fastqsanger.gz | |||
| SRR2028013.fastq.gz | Fastqsanger.gz | |||
| SRR2028014.fastq.gz | Fastqsanger.gz |
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Project description:Acute myeloid leukemia (AML) is characterized by a marked genetic heterogeneity, which complicates the development of novel therapeutics. The delineation of pathways essential within the patient-individual mutational background might overcome this limitation and facilitate personalized treatment. We report the results of a large-scale lentiviral loss-offunction RNA-interference-(RNAi)-screen in primary leukemic cells. Stringent validation identified six genes (BNIPL1, ROCK1, RPS13, STK3, SNX27, WDHD1) whose knockdown impaired growth and viability of the cells. Dependence on these genes was not caused by mutation or overexpression and while some of the candidates seemed to be rather patientspecific, others were essential in cells isolated from other AML patients. In addition to the phenotype observed after ROCK1 knockdown, treatment with the approved ROCK-inhibitor fasudil resulted in increased apoptosis and decreased viability of primary AML cells. In contrast to observations in some other malignancies, ROCK1-inhibition did not foster growth of immature malignant progenitors; but was also toxic to this cell fraction in feeder-co-culture and xenotransplantion experiments, indicating a distinct effect of ROCK1 inhibition on leukemic progenitors. We conclude that large scale RNAi screens in primary patient-derived cells are feasible and can complement other methods for personalized cancer therapies, such as expression and mutation profiling. Large-scale lentiviral loss-of-function shRNA screen in primary leukemic cells with two time points, exome sequencing of primary leukemic cells, and a gene expression profiling of primary cells from four leukemic and three healthy samples.
2015-05-16 | E-GEOD-68925 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) is characterized by a marked genetic heterogeneity, which complicates the development of novel therapeutics. The delineation of pathways essential within the patient-individual mutational background might overcome this limitation and facilitate personalized treatment. We report the results of a large-scale lentiviral loss-offunction RNA-interference-(RNAi)-screen in primary leukemic cells. Stringent validation identified six genes (BNIPL1, ROCK1, RPS13, STK3, SNX27, WDHD1) whose knockdown impaired growth and viability of the cells. Dependence on these genes was not caused by mutation or overexpression and while some of the candidates seemed to be rather patientspecific, others were essential in cells isolated from other AML patients. In addition to the phenotype observed after ROCK1 knockdown, treatment with the approved ROCK-inhibitor fasudil resulted in increased apoptosis and decreased viability of primary AML cells. In contrast to observations in some other malignancies, ROCK1-inhibition did not foster growth of immature malignant progenitors; but was also toxic to this cell fraction in feeder-co-culture and xenotransplantion experiments, indicating a distinct effect of ROCK1 inhibition on leukemic progenitors. We conclude that large scale RNAi screens in primary patient-derived cells are feasible and can complement other methods for personalized cancer therapies, such as expression and mutation profiling.
2015-05-16 | GSE68925 | GEO
Project description:Acute myeloid leukemia (AML) remains a challenging hematological malignancy with poor prognosis and limited treatment options. Post-therapy relapse, particularly driven by leukemic stem cells (LSCs), contributes to therapeutic failure and adverse outcome. Here, we investigated the role of quiescence and its associated molecular mechanisms in AML pathogenesis and identified potential vulnerabilities for therapeutic intervention. We found that quiescent AML cells, enriched for LSC functions, exhibited a distinct gene set that served as a significant prognostic factor for poor outcomes in AML patients. Furthermore, quiescent cells displayed heightened autophagic activity, with a reliance on ferritinophagy, a selective form of autophagy mediated by Nuclear Receptor Coactivator 4 (NCOA4), for iron bioavailability. Inhibition of NCOA4 genetically or chemically showed potent anti-leukemic effects, particularly targeting the LSC compartment. These findings uncover that ferritinophagy inhibition may represent a promising therapeutic strategy for patients with AML.
2024-06-13 | PXD042796 | Pride
Project description:MLL-rearranged acute myeloid leukemia (AML) remains a fatal disease with a high rate of relapse and therapeutic failure due to chemotherapy resistance. In analysis of our Affymetrix microarray profiling of human AML and normal control samples, we found that ALOX5 is especially down-regulated in MLL-rearranged AML. Our colony forming/replating and bone marrow transplantation (BMT) assays showed that Alox5 exhibited a moderate anti-tumor effect both in vitro and in vivo. Strikingly, leukemic cells with Alox5 overexpression showed a significantly higher sensitivity to the standard chemotherapeutic agents, i.e., doxorubicin (DOX) and cytarabine (Ara-C). The drug-sensitizing role of Alox5 was further confirmed in human and murine MLL-rearranged AML cell models in vitro, as well as in the in vivo MLL-rearranged AML BMT model coupled with treatment of “5+3” (i.e. DOX plus Ara-C) regimen. Our RNA-seq analysis showed that Stat and K-Ras signaling pathways were negatively correlated with Alox5 overexpression in MLL-AF9-leukemic blast cells, implying targeting those pathways likely contributes to Alox5’s functions. Collectively, our work shows that ALOX5 plays a moderate anti-tumor role and functions as a drug sensitizer, with a therapeutic potential, in MLL-rearranged AML.
2017-06-09 | GSE94840 | GEO
Project description:All-trans-retinoic acid (ATRA) has been successfully used in therapy of acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML) but the response of non-APL AML cases to ATRA-based treatment has been poor. Here we show that, via epigenetic reprogramming, inhibitors of LSD1/KDM1 demethylase including tranylcypromine (TCP) unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to an increase in genome-wide H3 lysine4 dimethylation (H3K4me2) but did increase H3K4me2 and expression of myeloid differentiation-associated genes. Importantly, treatment with ATRA plus TCP dramatically diminished engraftment of primary human AML cells in vivo in NOD.SCID mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP co-treatment 15 days post-engraftment of human AML cells in NOD.SCID gamma mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect, which was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for novel combinatorial therapies of AML. Overall, 30 specimens derived from HL-60 or TEX cell line were treated with drugs and hybridized to Illumina HumanHT-12 gene expression arrays.
2012-03-14 | E-GEOD-34672 | biostudies-arrayexpress
Project description:All-trans-retinoic acid (ATRA) has been successfully used in therapy of acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML) but the response of non-APL AML cases to ATRA-based treatment has been poor. Here we show that, via epigenetic reprogramming, inhibitors of LSD1/KDM1 demethylase including tranylcypromine (TCP) unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to an increase in genome-wide H3 lysine4 dimethylation (H3K4me2) but did increase H3K4me2 and expression of myeloid differentiation-associated genes. Importantly, treatment with ATRA plus TCP dramatically diminished engraftment of primary human AML cells in vivo in NOD.SCID mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP co-treatment 15 days post-engraftment of human AML cells in NOD.SCID gamma mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect, which was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for novel combinatorial therapies of AML. ChIP-seq was used to study the effects of ATRA, TCP and ATRA/TCP treatment on H3K4 dimethylation. In addition to the three treatment samples, two reference samples were processed: (i) An untreated sample using the same anti-H3K4me2 antibody and an untreated sample using IgG. These five sequencing experiments were conducted using HL-60 cells and TEX cells, leading to 10 ChIP-seq samples in total.
2012-03-14 | E-GEOD-34725 | biostudies-arrayexpress
Project description:The overall outcome of patients with acute myeloid leukemia (AML) remains poor and more effective strategies are urgently needed. Adefovir dipivoxil (ADV) is an oral prodrug of the nucleotide analogue adefovir that inhibits viral DNA polymerase and is a Food and Drug Administration (FDA)-approved drug for the treatment of hepatitis B virus. Preliminary evidence of the anti-leukemic activity of ADV was recently reported in a patient with acute promyelocytic leukemia. Herein we report on the anti-leukemic activity of ADV, alone and in combination with venetoclax (VEN), an oral FDA-approved BCL-2 inhibitor, for the treatment of AML. We observed a significant increase in apoptosis and reduction of cell growth both in AML cell lines and CD34+ blasts, but not in healthy donor CD34+ cells, after exposure to ADV. The combination of ADV and VEN had synergistic anti-leukemic activity and significantly reduced leukemia stem cell (LSC) burden and prolonged survival of AML murine (i.e., MllPTD/WT/Flt3ITD/ITD) and patient derived xenograft (PDX) models, likely by interfering with the bioenergetic metabolism of leukemic blasts and decreasing their apoptotic threshold. Our results provide a rationale for translating this “all oral” regimen to the clinic for treatment of AML patients, especially those requiring low intensity therapy.
2024-03-24 | GSE261921 | GEO
Project description:Epigenetic alterations contribute to leukemogenesis in childhood acute myeloid leukemia (AML). We used RNAi screens of AML cells together with non-transformed bone marrow cells and identified CHD4 as being required for AML maintenance. RNAi and CRISPR-Cas9 approaches, showed that CHD4 is essential for cell growth of leukemic cells in vitro, and disease progression in vivo, including primary childhood AML cells. Loss of function of CHD4 arrests AML cells in the G0 phase of the cell cycle, which is associated with downregulation of MYC and its target genes. Conversely, CHD4 suppression is not essential for normal blood cells. Taken together, our results identify CHD4 as a potential therapeutic target in childhood AML.
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Project description:Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known how mutant NPM1 (NPM1mut) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1mut AML. Using a CRISPR-Cas9 genome editing domain screen, we show NPM1mut AML to be exceptionally dependent on the menin binding site in MLL1. Pharmacological small-molecule inhibition of the menin-MLL protein interaction had profound anti-leukemic activity in human and murine models of NPM1mut AML in vitro and in vivo. Combined pharmacological inhibition of menin-MLL and DOT1L resulted in dramatic suppression of HOX and FLT3 expression, induction of differentiation, and superior activity against NPM1mut leukemia. Together, MLL1 and DOT1L are chromatin regulators that control HOX, MEIS1 and FLT3 expression and are therapeutic targets in NPM1mut AML. Combinatorial small-molecule inhibition has synergistic on target activity and constitutes a novel therapeutic concept for this common AML subtype. RNA sequencing data of the human AML cell lines OCI-AML2 and OCI-AML3 comparing EPZ004777 [10µM] drug treatment versus DMSO vehicle control; experiments performed in biological triplicates.
2016-08-22 | E-GEOD-85107 | biostudies-arrayexpress
Project description:Combined gene expression and DNA occupancy profiling identifies JAK/STAT signaling as a valid therapeutic target of t(8;21) AML t(8;21) is commonly associated with acute myeloid leukemia (AML). The resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression and promoter occupancy profiling using a primary leukemia initiating cell-enriched population induced by AML1-ETO9a (AE9a). CD45, a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is greatly downregulated; furthermore JAK1 and JAK2 are upregulated in these leukemia cells. Consequently, JAK/STAT signaling is enhanced in the AE9a leukemia cells. Importantly, AE9a leukemia cells are highly susceptible to perturbation of JAK/STAT signaling, and a JAK2-selective inhibitor, TG101209, effectively targets these leukemia cells in vivo, suggesting the potential efficacy of JAK2 inhibitors in treating t(8;21) AML. Wild-type or AE9a leukemic samples in triplicate.
2012-09-04 | E-GEOD-15195 | biostudies-arrayexpress