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Duy C , Li M , Teater M , Meydan C , Garrett-Bakelman FE , Lee TC , Chin CR , Durmaz C , Kawabata KC , Dhimolea E , Mitsiades CS , Doehner H , D'Andrea RJ , Becker MW , Paietta EM , Mason CE , Carroll M , Melnick AM
Chemotherapy induces senescence-like resilient cells capable of initiating AML recurrence
Cancer Discov. 2021 Jun;11(6) :1542-1561
PMID: 33500244    PMCID: PMC8178167    URL: https://www.ncbi.nlm.nih.gov/pubmed/33500244
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Acute myeloid leukemia (AML) patients 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-seq 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.
2159-8290 Duy, Cihangir Li, Meng Teater, Matt Orcid: 0000-0001-9415-1659 Meydan, Cem Orcid: 0000-0002-0663-6216 Garrett-Bakelman, Francine E Orcid: 0000-0002-4771-628x Lee, Tak C Chin, Christopher R Orcid: 0000-0002-2140-3197 Durmaz, Ceyda Kawabata, Kimihito C Dhimolea, Eugen Mitsiades, Constantine S Doehner, Hartmut D'Andrea, Richard J Becker, Michael W Paietta, Elisabeth M Mason, Christopher E Orcid: 0000-0002-1850-1642 Carroll, Martin Melnick, Ari M Orcid: 0000-0002-8074-2287 Journal Article United States Cancer Discov. 2021 Jan 26:candisc.1375.2020. doi: 10.1158/2159-8290.CD-20-1375.