Similar Datasets
Project description:In acute myeloid leukemias (AML), chemotherapy is frequently followed by disease relapse, yet the mechanism by which AML reemerges is not fully understood. We hypothesized that chemotherapy induces senescence-like dormancy that facilitates survival to genotoxic exposure, allowing AML cells to endure treatment in a transiently dormant state while retaining potential for leukemic repopulation. Here, we show that primary AML cells exhibit hallmark senescence features following treatment with cytarabine (AraC), including growth arrest, increased cellular granularity, senescence-associated-β-galactosidase (SA-β-gal) activity, and senescence-associated transcriptomic alterations. Induction of AraC-induced premature senescence was regulated by the ATR kinase activity and mediated stress-survival. High-throughput single cell RNA (scRNA)-seq analysis of primary AML cells ex vivo and in vivo following chemotherapy suggest active transcriptional programming towards senescent-like dormancy instead of enrichment for leukemia stem cells (LSCs). scRNA-seq of sorted AraC-induced premature senescent AML cells demonstrated a heterogenous population including a fraction of cells with simultaneous expression of dormancy- and senescence-associated gene signatures. Xenotransplantation of AraC-induced premature senescent AML cells into mice demonstrated that senescent-like AML cells maintain leukemia-repopulating potential. Altogether, we propose a mechanism of AML relapse whereby AML cells tolerate chemotherapy via acquisition of a transient senescent-like state.
2021-03-14 | GSE146592 | GEO
Project description:In acute myeloid leukemias (AML), chemotherapy is frequently followed by disease relapse, yet the mechanism by which AML reemerges is not fully understood. We hypothesized that chemotherapy induces senescence-like dormancy that facilitates survival to genotoxic exposure, allowing AML cells to endure treatment in a transiently dormant state while retaining potential for leukemic repopulation. Here, we show that primary AML cells exhibit hallmark senescence features following treatment with cytarabine (AraC), including growth arrest, increased cellular granularity, senescence-associated-β-galactosidase (SA-β-gal) activity, and senescence-associated transcriptomic alterations. Induction of AraC-induced premature senescence was regulated by the ATR kinase activity and mediated stress-survival. High-throughput single cell RNA (scRNA)-seq analysis of primary AML cells ex vivo and in vivo following chemotherapy suggest active transcriptional programming towards senescent-like dormancy instead of enrichment for leukemia stem cells (LSCs). scRNA-seq of sorted AraC-induced premature senescent AML cells demonstrated a heterogenous population including a fraction of cells with simultaneous expression of dormancy- and senescence-associated gene signatures. Xenotransplantation of AraC-induced premature senescent AML cells into mice demonstrated that senescent-like AML cells maintain leukemia-repopulating potential. Altogether, we propose a mechanism of AML relapse whereby AML cells tolerate chemotherapy via acquisition of a transient senescent-like state.
2021-03-14 | GSE146542 | GEO
Project description:In acute myeloid leukemias (AML), chemotherapy is frequently followed by disease relapse, yet the mechanism by which AML reemerges is not fully understood. We hypothesized that chemotherapy induces senescence-like dormancy that facilitates survival to genotoxic exposure, allowing AML cells to endure treatment in a transiently dormant state while retaining potential for leukemic repopulation. Here, we show that primary AML cells exhibit hallmark senescence features following treatment with cytarabine (AraC), including growth arrest, increased cellular granularity, senescence-associated-β-galactosidase (SA-β-gal) activity, and senescence-associated transcriptomic alterations. Induction of AraC-induced premature senescence was regulated by the ATR kinase activity and mediated stress-survival. High-throughput single cell RNA (scRNA)-seq analysis of primary AML cells ex vivo and in vivo following chemotherapy suggest active transcriptional programming towards senescent-like dormancy instead of enrichment for leukemia stem cells (LSCs). scRNA-seq of sorted AraC-induced premature senescent AML cells demonstrated a heterogenous population including a fraction of cells with simultaneous expression of dormancy- and senescence-associated gene signatures. Xenotransplantation of AraC-induced premature senescent AML cells into mice demonstrated that senescent-like AML cells maintain leukemia-repopulating potential. Altogether, we propose a mechanism of AML relapse whereby AML cells tolerate chemotherapy via acquisition of a transient senescent-like state.
2021-03-14 | GSE145061 | GEO
Project description:In acute myeloid leukemias (AML), chemotherapy is frequently followed by disease relapse, yet the mechanism by which AML reemerges is not fully understood. We hypothesized that chemotherapy induces senescence-like dormancy that facilitates survival to genotoxic exposure, allowing AML cells to endure treatment in a transiently dormant state while retaining potential for leukemic repopulation. Here, we show that primary AML cells exhibit hallmark senescence features following treatment with cytarabine (AraC), including growth arrest, increased cellular granularity, senescence-associated-β-galactosidase (SA-β-gal) activity, and senescence-associated transcriptomic alterations. Induction of AraC-induced premature senescence was regulated by the ATR kinase activity and mediated stress-survival. High-throughput single cell RNA (scRNA)-seq analysis of primary AML cells ex vivo and in vivo following chemotherapy suggest active transcriptional programming towards senescent-like dormancy instead of enrichment for leukemia stem cells (LSCs). scRNA-seq of sorted AraC-induced premature senescent AML cells demonstrated a heterogenous population including a fraction of cells with simultaneous expression of dormancy- and senescence-associated gene signatures. Xenotransplantation of AraC-induced premature senescent AML cells into mice demonstrated that senescent-like AML cells maintain leukemia-repopulating potential. Altogether, we propose a mechanism of AML relapse whereby AML cells tolerate chemotherapy via acquisition of a transient senescent-like state.
2021-03-14 | GSE146590 | GEO
Project description:Acute myeloid leukemia cells resist chemotherapy through a transient senescence-like state
| PRJNA610828 | ENA
Project description:Acute myeloid leukemia cells resist chemotherapy through a transient senescence-like state [PDX]
| PRJNA610898 | ENA
Project description:Acute myeloid leukemia cells resist chemotherapy through a transient senescence-like state [Array]
| PRJNA610835 | ENA
Project description:Acute myeloid leukemia cells resist chemotherapy through a transient senescence-like state [RNA-seq]
| PRJNA605820 | ENA
Project description:Acute myeloid leukemia cells resist chemotherapy through a transient senescence-like state [scRNA-seq]
| PRJNA610895 | ENA
Project description:Drug resistance constitutes one of the main obstacles for clinical recovery of acute myeloid leukemia (AML) patients. Therefore, the treatment of AML requires new strategies, such as adding a third drug. To address whether GATA2 could act as a regulator of chemotherapy resistance in human leukemia cells, we observed KG1a cells and clinical patients' AML cells with a classic drug (Cerubidine) and Gefitinib. After utilizing chemotherapy, the expression of GATA2 and its target genes (EVI, SCL and WT1) in surviving AML cells and KG1a cells were significantly enhanced to double and quadrupled compared to its original level respectively. Furthermore, with continuous chemotherapeutics, AML cells with GATA2 knockdown or treated with GATA2 inhibitor (K1747) almost eliminated with dramatically reduced expression of WT1, SCL, EVI, and significantly increased apoptotic population. Therefore, we propose that reducing GATA2 expression or inhibition of its transcription activity can relieve the drug resistance of acute myeloid leukemia cells and it would be helpful for eliminating the leukemia cells in patients.
| S-EPMC5256934 | biostudies-literature