Project description:Accumulating evidence indicates that patient- derived organoids (PDOs) can predict drug responses in the clinic. Metastasis is the main cause of death in colorectal cancer patients, and the treatment of patients with liver metastasis remains poor. Tumor heterogeneity is the cause of treatment failure. In this study, we aim the investigate the consistency of drug sensitivity for the matched primary and metastatic tumor in patients with liver metastasis.

| 2400343 | ecrin-mdr-crc

Joint Addiction, Aging, and Mental Health Data Access Committee General Research Use Datasets (GSR restricted) Collection

Project description:Joint Addiction, Aging, and Mental Health Data Access Committee General Research Use Datasets (GSR restricted) Collection

| PRJNA1018662 | ENA

Joint Addiction, Aging, and Mental Health Data Access Committee General Research Use Datasets (GSR restricted) Collection

Project description:Joint Addiction, Aging, and Mental Health Data Access Committee General Research Use Datasets (GSR restricted) Collection

| PRJNA1018664 | ENA

Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment II

Project description:Decitabine (DAC) is used clinically for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells shows that mitotic regulation plays a pivotal role in DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations and antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, the overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation, while highlighting the potent activity of DAC to perturb mitosis through aberrant DNMT1-DNA covalent bonds.

2023-08-14 | GSE240570 | GEO

Treatment of AML patient samples with decitabine

Project description:Genome wide DNA methylation profiling of AML patient samples treated with PBS or DAC. The Illumina Infinium 450 Human DNA methylation was used to examine the methylation profile of 8 patient samples and 2 cell lines. Genome wide DNA methylation profiling of AML xenografts treated with either PBS control or with decitacine (DAC) alone, cytarabine (Ara-C) alone, DAC and Ara-C together (D+A), DAC followed by Ara-C (D/A) or with Ara-C followed by DAC (A/D).

2013-03-06 | GSE44830 | GEO

Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment

Project description:Decitabine (DAC) is used clinically for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). To elucidate its exact mechanism of action, we performed a genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells and revealed that mitotic regulation plays a pivotal role in DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations and antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, the overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to perturb mitosis through aberrant DNMT1-DNA covalent bonds. This clinically revised mode of action is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway.

2023-08-14 | GSE240439 | GEO

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