Hierarchical Lineage Tracing Reveals Diverse Pathways of AML Treatment Resistance [scRNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1222993 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32325120_1.fastq.gz | Fastqsanger.gz | |||
| SRR32325120_2.fastq.gz | Fastqsanger.gz | |||
| SRR32325121_1.fastq.gz | Fastqsanger.gz | |||
| SRR32325121_2.fastq.gz | Fastqsanger.gz | |||
| SRR32325122_1.fastq.gz | Fastqsanger.gz |
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Project description:Hierarchical Lineage Tracing Reveals Diverse Pathways of AML Treatment Resistance [DNA-seq]
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Project description:Cancer cells adapt to treatment, leading to the emergence of clones that are more aggressive and resistant to anti-cancer therapies. We have a limited understanding of the evolution of treatment resistance as we have lacked technologies to map the evolution of cancer under the selective pressures. To address this, we developed a hierarchical, dynamic lineage tracing method called FLARE (Following Lineage Adaptation and Resistance Evolution). We use this technique to track the progression of acute myeloid leukemia (AML) cell lines through exposure to Cytarabine (AraC), a front-line treatment in AML, in vitro and in vivo. We map distinct cellular lineages in murine and human AML cell lines that are predisposed to AraC persistence and/or resistance via upregulation of cell adhesion and motility pathways. Additionally, we highlight heritable increased expression of immunoproteasome 11S regulatory cap subunits as a potential mechanism aiding AML cell survival, proliferation, and immune escape in vivo. Finally, we validate the clinical relevance of these signatures in the TARGET-AML cohort, with a bisected response in blood and bone marrow. Our findings reveal a broad spectrum of resistance signatures attributed to significant cell transcriptional changes, and we expect this high-resolution profiling of treatment response to be a useful tool to dissect the evolution of treatment response in a wide range of tumor types.
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Project description:Cancer cells adapt to treatment, leading to the emergence of clones that are more aggressive and resistant to anti-cancer therapies. We have a limited understanding of the development of treatment resistance as we lack technologies to map the evolution of cancer under the selective pressure of treatment. To address this, we developed a hierarchical, dynamic lineage tracing method called FLARE (Following Lineage Adaptation and Resistance Evolution). We use this technique to track the progression of acute myeloid leukemia (AML) cell lines through exposure to Cytarabine (AraC), a front-line treatment in AML, in vitro and in vivo. We map distinct cellular lineages in murine and human AML cell lines predisposed to AraC persistence and/or resistance via the upregulation of cell adhesion and motility pathways. Additionally, we highlight the heritable expression of immunoproteasome 11S regulatory cap subunits as a potential mechanism aiding AML cell survival, proliferation, and immune escape in vivo. Finally, we validate the clinical relevance of these signatures in the TARGET-AML cohort, with a bisected response in blood and bone marrow. Our findings reveal a broad spectrum of resistance signatures attributed to significant cell transcriptional changes. To our knowledge, this is the first application of dynamic lineage tracing to unravel treatment response and resistance in cancer, and we expect FLARE to be a valuable tool in dissecting the evolution of resistance in a wide range of tumor types.
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Project description:Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells; The genetic programs that promote retention of self-renewing leukemia stem cells (LSCs) at the apex of cellular hierarchies in acute myeloid leukemia (AML) are not known. In a mouse model of human AML, LSCs exhibit variable frequencies that correlate with the initiating MLL oncogene and are maintained in a self-renewing state by a transcriptional sub-program more akin to that of embryonic stem cells (ESCs) than adult stem cells. The transcription/chromatin regulatory factors Myb, Hmgb3 and Cbx5 are critical components of the program and suffice for Hoxa/Meis-independent immortalization of myeloid progenitors when co-expressed, establishing the cooperative and essential role of an ESC-like LSC maintenance program ancillary to the leukemia initiating MLL/Hox/Meis program. Enriched expression of LSC maintenance and ESC-like program genes in normal myeloid progenitors and poor prognosis human malignancies links the frequency of aberrantly self-renewing progenitor-like cancer stem cells to prognosis in human cancer. Experiment Overall Design: Refer to individual Series Experiment Overall Design: This SuperSeries is composed of the following subset Series: Experiment Overall Design: GSE13690: Gene expression profiling of murine MLL leukemias (whole BM) Experiment Overall Design: GSE13692: Expression profiling of MLL-AF10 myeloid leukemia cellular subsets Experiment Overall Design: GSE13693: Gene expression profiling of normal mouse myeloid cell populations
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Project description:Cardiac fibroblasts convert to myofibroblasts with injury to mediate healing after acute myocardial infarction and to mediate long-standing fibrosis with chronic disease. Myofibroblasts remain a poorly defined cell-type in terms of their origins and functional effects in vivo. Methods: Here we generate Postn (periostin) gene-targeted mice containing a tamoxifen inducible Cre for cellular lineage tracing analysis. This Postn allele identifies essentially all myofibroblasts within the heart and multiple other tissues. Results: Lineage tracing with 4 additional Cre-expressing mouse lines shows that periostin-expressing myofibroblasts in the heart derive from tissue-resident fibroblasts of the Tcf21 lineage, but not endothelial, immune/myeloid or smooth muscle cells. Deletion of periostin+ myofibroblasts reduces collagen production and scar formation after myocardial infarction. Periostin-traced myofibroblasts also revert back to a less activated state upon injury resolution. Conclusions: Our results define the myofibroblast as a periostin-expressing cell-type necessary for adaptive healing and fibrosis in the heart, which arises from Tcf21+ tissue-resident fibroblasts. Fluidigm C1 whole genome transcriptome analysis of lineage mapped cardiac myofibroblasts
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