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TitleChemotherapy Induces Senescence-Like Resilient Cells Capable of Initiating AML Recurrence.
Publication TypeJournal Article
Year of Publication2021
AuthorsDuy, Cihangir, Li Meng, Teater Matt, Meydan Cem, Garrett-Bakelman Francine E., Lee Tak C., Chin Christopher R., 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., Carroll Martin, and Melnick Ari M.
JournalCancer Discov
Volume11
Issue6
Pagination1542-1561
Date Published2021 06
ISSN2159-8290
KeywordsAnimals, Cell Line, Tumor, Humans, Leukemia, Myeloid, Acute, Mice, Mice, Inbred NOD, Neoplasm Recurrence, Local, Neoplastic Stem Cells, Phenotype, Remission Induction
Abstract

<p>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 and . This is accompanied by induction of senescence/inflammatory and embryonic diapause transcriptional programs, with downregulation of and leukemia stem cell genes. Single-cell RNA sequencing suggested depletion of leukemia stem cells and , 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..</p>

DOI10.1158/2159-8290.CD-20-1375
Alternate JournalCancer Discov
PubMed ID33500244
PubMed Central IDPMC8178167
Grant ListR01 CA198089 / CA / NCI NIH HHS / United States
K08 CA169055 / CA / NCI NIH HHS / United States
R35 CA220499 / CA / NCI NIH HHS / United States
U24 CA196172 / CA / NCI NIH HHS / United States
R01 CA196664 / CA / NCI NIH HHS / United States
U10 CA180820 / CA / NCI NIH HHS / United States
UG1 CA233332 / CA / NCI NIH HHS / United States
U10 CA180827 / CA / NCI NIH HHS / United States
U01 CA225730 / CA / NCI NIH HHS / United States
R01 CA050947 / CA / NCI NIH HHS / United States