Contributions
Abstract: EP454
Type: e-Poster
Background
In acute myeloid leukemia (AML), chemotherapy is frequently followed by disease relapse, yet the mechanism by which AML reemerges is not fully understood.
Aims
We hypothesized that chemotherapy-induced senescence facilitates survival to genotoxic exposure, allowing AML cells to endure treatment in a transiently dormant state while retaining potential for leukemic repopulation.
Methods
Bulk and single-cell RNA-seq analyses of primary AML specimens ex vivo, in mice and in patients. Ex vivo chemotherapy exposure and relapse models using primary AML organoid models. In vivo relapse models using patient-derived xenograft models in NSG mice. Viable monitoring and selection of senescent cells for funtional experiments. Immunoblots, flow cytometry and integrative analysis.
Results
Herein, we show that primary AML cells enter into a senescent-like state following treatment with chemotherapy in vitro and in vivo. This is accompanied by induction of senescence/inflammatory and embryonic diapause transcriptional programs, with downregulation of MYC and leukemia stem cell genes. Single-cell RNA-seq showed depletion of leukemia stem cells in vitro and in vivo, and enrichment for subpopulations of cells manifesting distinct senescent-like programs. This senescence effect was reversible and conferred superior colony forming and engraftment potential. Entry into this senescence-like state was dependent on ATR, and persistence of AML cells was severely impaired by ATR inhibitors.
Conclusion
Altogether, we propose that AML relapse is caused by induction of an ATR-dependent transient senescent state rather than persistence of stem-like cells. Upon recovery, these senescent cells give rise to relapsed AML with increased fractions of cells with stem cell potential.
Session topic: 03. Acute myeloid leukemia - Biology & Translational Research
Abstract: EP454
Type: e-Poster
Background
In acute myeloid leukemia (AML), chemotherapy is frequently followed by disease relapse, yet the mechanism by which AML reemerges is not fully understood.
Aims
We hypothesized that chemotherapy-induced senescence facilitates survival to genotoxic exposure, allowing AML cells to endure treatment in a transiently dormant state while retaining potential for leukemic repopulation.
Methods
Bulk and single-cell RNA-seq analyses of primary AML specimens ex vivo, in mice and in patients. Ex vivo chemotherapy exposure and relapse models using primary AML organoid models. In vivo relapse models using patient-derived xenograft models in NSG mice. Viable monitoring and selection of senescent cells for funtional experiments. Immunoblots, flow cytometry and integrative analysis.
Results
Herein, we show that primary AML cells enter into a senescent-like state following treatment with chemotherapy in vitro and in vivo. This is accompanied by induction of senescence/inflammatory and embryonic diapause transcriptional programs, with downregulation of MYC and leukemia stem cell genes. Single-cell RNA-seq showed depletion of leukemia stem cells in vitro and in vivo, and enrichment for subpopulations of cells manifesting distinct senescent-like programs. This senescence effect was reversible and conferred superior colony forming and engraftment potential. Entry into this senescence-like state was dependent on ATR, and persistence of AML cells was severely impaired by ATR inhibitors.
Conclusion
Altogether, we propose that AML relapse is caused by induction of an ATR-dependent transient senescent state rather than persistence of stem-like cells. Upon recovery, these senescent cells give rise to relapsed AML with increased fractions of cells with stem cell potential.
Session topic: 03. Acute myeloid leukemia - Biology & Translational Research
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