Expression profiling with RNA-seq between mouse AML cells with or without chemotherapy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE161490 | GEO | 2020/11/29
REPOSITORIES: GEO
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Project description:We reported the expression profiling between mTORC1 high and low mouse AML cells with MLL-AF9 utilizing a novel fluorescent probe named mVenus-TOSI (TOr-Signal-Indicator). For this purpose, 3 mTOR high (mVenus low) and 4 mTOR low (mVenus high) Mouse AML cells were harvested from 4 mice. The transcriptomic profiles were distinctive and gene ontology analysis revealed that mTORC1 activity was associated with differentially expressed immune response and metabolism related genes. Further, gene signature enrichment analysis (GSEA) validated that the mTORC1 signal signature correlated with mTORC1 activity and that leukemia stem cell (LSC), Myc, and cell cycle related signatures were enriched in mTORC1 high cells.
2020-11-29 | GSE161362 | GEO
Project description:There are two possible mechanisms for the shift of gene expression to a high mTORC1 activity signature after chemotherapy; one is the selection of mTORC1 high cells and the second is the induction of mTORC1 activity following chemotherapy. We assessed these two possible scenarios by introducing genetic barcodes using the ClonTracer library that allowed for clonal tracking of ~0.2 million AML cells. We found that a significant proportion of unique barcodes are represented in both the mTORC1 high and low cell populations. Since barcodes only infect a single cell which has to exist in a high or low state, a significant proportion of barcodes that are represented by cells in both states suggests that induction occurs. Otherwise the proportion should be close to an extreme (0 or 1) meaning most of the populations exist only in mTORC1 high or mTORC1 low states. Additionally, clonal abundance based on barcodes revealed more similarity with respect to the cumulative proportion of represented barcodes between mTORC1 high and low cells in treated cohorts compared with non-treated cohorts. These data suggest a more similar distribution of mTORC1 high and low cells in these populations which would arise primarily due to induction rather than selection.
2020-11-29 | GSE162153 | GEO
Project description:Purpose Acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the rapid clonal expansion of abnormally differentiated myeloid progenitor cells residing in a complex microenvironment. However, the immune cell types, status, and genome profile of the peripheral blood mononuclear cell (PBMC) microenvironment in AML patients after chemotherapy are poorly understood. In order to explore the immune microenvironment of AML patients after chemotherapy, we conducted this study for providing insights into precision medicine and immunotherapy of AML. Methods In this study, we used single-cell RNA sequencing (scRNA-seq) to analyse the PBMC microenvironment from five AML patients treated with different chemotherapy regimens and six healthy donors. We compared the cell compositions in AML patients and healthy donors, and performed gene set enrichment analysis (GSEA), CellPhoneDB, and copy number variation (CNV) analysis. Results Using scRNA-seq technology, 91,772 high quality cells of 44,950 PBMCs from AML patients and 46,822 PBMCs from healthy donors were classified as 14 major cell clusters. Our study revealed the sub-cluster diversity of T cells, natural killer (NK) cells, monocytes, dendritic cells (DCs), and haematopoietic stem cell progenitors (HSC-Prog) in AML patients under chemotherapy. NK cells and monocyte-DCs showed significant changes in transcription factor expression and chromosome copy number variation (CNV). We also observed significant heterogeneity in CNV and intercellular interaction networks in HSC-Prog cells. Conclusion Our results elucidated the PBMC single-cell landscape and provided insights into precision medicine and immunotherapy for treating AML.
2023-08-31 | GSE235857 | GEO
Project description:Expression profiling with RNA-seq between mouse AML cells with or without chemotherapy
| PRJNA678444 | ENA
Project description:To explore the effect of Shp-1 deletion on single-cell resolution, we profiled Shp-1f/f and Shp-1Δ/Δ AML cells from the BM of MLL-AF9 mice with or without chemotherapy using single-cell RNA sequencing (scRNA-seq).
2023-11-22 | GSE244234 | GEO
Project description:The frequent occurrence of persistent or relapsed disease following induction chemotherapy in AML necessitates a better understanding of the clonal relationship of AML in various disease phases. In this study, we employed SNP 6.0 array-based genomic profiling of acquired copy number aberrations (aCNA) and copy neutral LOH (cnLOH) together with sequence analysis of recurrently mutated genes to characterize paired AML genomes. We analyzed 28 AML sample pairs from patients that achieved complete remission with chemotherapy and subsequently relapsed and 11 sample pairs from patients with persistent disease following induction chemotherapy. Through review of aCNA/cnLOH and gene mutation profiles in informative cases we demonstrate that relapsed AML invariably represents reemergence or evolution of a founder clone. Furthermore, all individual aCNA or cnLOH detected at presentation persisted at relapse indicating that this lesion type is proximally involved in AML evolution. Analysis of informative paired persistent AML disease samples uncovered cases with two coexisting dominant clones of which at least one was chemotherapy sensitive and one resistant, respectively. These data support the conclusion that incomplete eradication of AML founder clones rather than stochastic emergence of fully unrelated novel clones underlies AML relapse and persistence with direct implications for clinical AML research This study is based on 39 patients with AML for which either paired enrollment or relapse samples or persistent disease samples were available. The patients were enrolled into this study at the University of Michigan Comprehensive Cancer Center. The study was approved by the University of Michigan Institutional Review Board (IRBMED #2004-1022) and written informed consent was obtained from all patients prior to enrollment. Genomic DNA was extracted from purified AML blasts and paired buccal cells. DNA thus obtained was hybridized to Affymetrix SNP 6.0 arrays. Note: There is no normal sample available for MIAML015.
2013-02-12 | E-GEOD-41646 | biostudies-arrayexpress
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 | GSE146590 | 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.
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