Chemotherapy Induces Senescence-Like Resilient Cells Capable of Initiating AML Recurrence

Author:

Duy Cihangir123,Li Meng3,Teater Matt3ORCID,Meydan Cem4ORCID,Garrett-Bakelman Francine E.356ORCID,Lee Tak C.3,Chin Christopher R.4ORCID,Durmaz Ceyda4,Kawabata Kimihito C.3,Dhimolea Eugen789,Mitsiades Constantine S.789,Doehner Hartmut10,D'Andrea Richard J.11,Becker Michael W.12,Paietta Elisabeth M.13,Mason Christopher E.4ORCID,Carroll Martin14,Melnick Ari M.3ORCID

Affiliation:

1. 1Cancer Signaling and Epigenetics Program, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

2. 2Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

3. 3Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medicine, New York, New York.

4. 4Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York.

5. 5Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia.

6. 6Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.

7. 7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

8. 8Harvard Medical School, Boston, Massachusetts.

9. 9Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

10. 10Universitätsklinikum Ulm, Ulm, Germany.

11. 11University of South Australia, Adelaide, Australia.

12. 12University of Rochester Medical Center, Rochester, New York.

13. 13Oncology, Montefiore Medical Center, Bronx, New York.

14. 14University of Pennsylvania, Philadelphia, Pennsylvania.

Abstract

Abstract Patients with acute myeloid leukemia (AML) frequently relapse after chemotherapy, yet the mechanism by which AML reemerges is not fully understood. Herein, we show that primary AML cells enter a senescence-like phenotype following 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 sequencing suggested depletion of leukemia stem cells in vitro and in vivo, and enrichment for subpopulations with distinct senescence-like cells. This senescence effect was transient and conferred superior colony-forming and engraftment potential. Entry into this senescence-like phenotype was dependent on ATR, and persistence of AML cells was severely impaired by ATR inhibitors. Altogether, we propose that AML relapse is facilitated by a senescence-like resilience phenotype that occurs regardless of their stem cell status. Upon recovery, these post-senescence AML cells give rise to relapsed AMLs with increased stem cell potential. Significance: Despite entering complete remission after chemotherapy, relapse occurs in many patients with AML. Thus, there is an urgent need to understand the relapse mechanism in AML and the development of targeted treatments to improve outcome. Here, we identified a senescence-like resilience phenotype through which AML cells can survive and repopulate leukemia. This article is highlighted in the In This Issue feature, p. 1307

Funder

NIH NCI

NIH

Publisher

American Association for Cancer Research (AACR)

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