TY - JOUR
T1 - Chemotherapy induces senescence-like resilient cells capable of initiating aml recurrence
AU - Duy, Cihangir
AU - Li, Meng
AU - Teater, Matt
AU - Meydan, Cem
AU - Garrett-Bakelman, Francine E.
AU - Lee, Tak C.
AU - Chin, Christopher R.
AU - Durmaz, Ceyda
AU - Kawabata, Kimihito C.
AU - Dhimolea, Eugen
AU - Mitsiades, Constantine S.
AU - Doehner, Hartmut
AU - D’andrea, Richard J.
AU - Becker, Michael W.
AU - Paietta, Elisabeth M.
AU - Mason, Christopher E.
AU - Carroll, Martin
AU - Melnick, Ari M.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021
Y1 - 2021
N2 - Patients with acute myeloid leukemia (AML) frequently relapse after chemother-apy, 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.
AB - Patients with acute myeloid leukemia (AML) frequently relapse after chemother-apy, 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.
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U2 - 10.1158/2159-8290.CD-20-1375
DO - 10.1158/2159-8290.CD-20-1375
M3 - Article
C2 - 33500244
AN - SCOPUS:85100598084
SN - 2159-8274
VL - 11
SP - 1542
EP - 1561
JO - Cancer discovery
JF - Cancer discovery
IS - 6
ER -