ACUTE MYELOID LEUKEMIA CELLS RESIST CHEMOTHERAPY THROUGH A TRANSIENT SENESCENCE-LIKE STATE
Author(s): ,
Cihangir Duy
Affiliations:
Weill Cornell Medicine,New York,United States
,
Meng Li
Affiliations:
Weill Cornell Medicine,New York,United States
,
Matt Teater
Affiliations:
Weill Cornell Medicine,New York,United States
,
Cem Meydan
Affiliations:
Weill Cornell Medicine,New York,United States
,
Francine Garrett-Bakelman
Affiliations:
University of Virginia School of Medicine,Charlottesville,United States;Weill Cornell Medicine,New York,United States
,
Christopher Chin
Affiliations:
Weill Cornell Medicine,New York,United States
,
Hartmut Döhner
Affiliations:
Universitätsklinikum Ulm,Ulm,Germany
,
Richard D'Andrea
Affiliations:
University of South Australia,Adelaide,Australia
,
Christopher Mason
Affiliations:
Weill Cornell Medicine,New York,United States
,
Martin Carroll
Affiliations:
University of Pennsylvania,Philadelphia,United States
Ari Melnick
Affiliations:
Weill Cornell Medicine,New York,United States
EHA Library. Duy C. 06/12/20; 294373; EP454
Cihangir Duy
Cihangir Duy
Contributions
Abstract

Abstract: EP454

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

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

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

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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