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

TNBC (PDX-WGS) - Data Access Committee at The Jackson laboratory

Project description:Data Access Committee EGAC00001002515

| EGAC00001002515 | EGA

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

SEER Remote Access Pilot Test Data (2018)

Project description:SEER Remote Access Pilot Test Data (2018)

| PRJNA625583 | ENA