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Cited by 253Acute Myeloid Leukemia ResearchTelomeres, Telomerase, and SenescenceHematopoietic Stem Cell Transplantation

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

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Duy, Cihangir, Li, Meng, Teater, Matt, Meydan, Cem, Garrett-Bakelman, Francine E., Lee, Tak C., Chin, Christopher R., Durmaz, Ceyda +10 more·2021·Cancer Discovery
DOI 10.1158/2159-8290.cd-20-1375PMC PMC8178167

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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

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  • Senescence-like resilient phenotypes induced by cytarabine were observed in cultured acute myeloid leukaemia cells.

    “Further supporting these findings, senescence-like resilient phenotypes induced by cytarabine were observed in cultured acute myeloid leukaemia cells that might hypothetically act as leukaemia- reinitiating stem cells and promote relapse in patients 191 .”

    From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [191]

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References 86 · Cited by 253

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Authors
Duy, C., Li, M., Teater, M., Meydan, C., Garrett-Bakelman, F. E., Lee, T. C., Chin, C. R., Durmaz, C., Kawabata, K. C., Dhimolea, E., Mitsiades, C. S., Doehner, H., D'Andrea, R. J., Becker, M. W., Paietta, E. M., Mason, C. E., Carroll, M., & Melnick, A. M.
Affiliations
  • Fox Chase Cancer Center (US)
  • Weill Cornell Medicine (US)
  • Broad Institute (US)
  • 10Universitätsklinikum Ulm, Ulm, Germany.
  • 11University of South Australia, Adelaide, Australia.
  • University of Rochester Medicine (US)
  • Montefiore Medical Center (US)
  • University of Pennsylvania (US)
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2021-01-26
Volume
11
Issue
6
Pages
1542-1561
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-20-1375
PMC
PMC8178167
OpenAlex
W3124870698
Cited by
253
References
86
Citations by year
2026: 36 · 2025: 42 · 2024: 50 · 2023: 56 · 2022: 47 · 2021: 22
FWCI
30.16
Type
journal article
Language
en
Open access
Locations
  • Cancer Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIH NCI (R01CA198089, CA233332)
  • NIH (R01 CA050947, CA196664)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
Keywords
acute myeloid leukemia, relapsed AML, chemotherapy-induced senescence, leukemia stem cells, ATR, ATR inhibitors, c-Myc, single-cell RNA sequencing, engraftment potential
MeSH terms
Animals, Humans, Neoplasm Recurrence, Local, Phenotype, Remission Induction, Neoplastic Stem Cells, Leukemia, Myeloid, Acute, Mice, Inbred NOD, Cell Line, Tumor, Mice

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