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 - Funding Information:
C. Duy reports grants from Leukemia and Lymphoma Society (LLS), ECOG, and NCI/NIH during the conduct of the study. C. Meydan reports personal fees from Onegevity Health outside the submitted work. C.S. Mitsiades reports grants from NIH/NCI, LLS, and Ludwig Center at Harvard during the conduct of the study; other support from Takeda, personal fees from Fate Therapeutics and Ionis Pharmaceuticals, grants from Janssen/Johnson & Johnson, TEVA, EMD Serono/Merck KGA, AbbVie, Karyopharm, Arch Oncology, Sanofi, and Nurix outside the submitted work; and C.S. Mitsiades have been as coinventor in several patent applications pertinent to the broader theme of resistance of different types of neoplasias to various therapeutics. R.J. D’Andrea reports grants from Takeda Pharmaceuticals and other support from Calli Biotech outside the submitted work. C.E. Mason is a cofounder of Onegev-ity. A.M. Melnick reports grants from Janssen, Daiichi Sankyo, and Sanofi during the conduct of the study; personal fees from Epizyme, Constellation, BMS, and Exo-therapeutics, and other support from KDAC outside the submitted work. No other disclosures were reported.
Funding Information:
We acknowledge the ECOG–ACRIN Cancer Research Group and the Weill Cornell Medicine Epigenomics Core for technical services. We thank Yaseswini Neelamraju for assistance with data submission to dbGap. This work is supported by the NCI of the NIH under the following award numbers: NIH/NCI R01CA198089 (A.M. Melnick and M. Carroll) and NIH/NCI UG1 CA233332 (A.M. Melnick). This work was supported by grants NIH R01 CA050947 (C.S. Mitsiades), CA196664 (C.S. Mitsiades), U01CA225730 (C.S. Mitsiades); Leukemia and Lymphoma Society (LLS) Scholar Award (C.S. Mitsiades); and Ludwig Center at Harvard (C.S. Mitsiades). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was further supported by LLS SCOR 7013-17 (A.M. Melnick) and U10CA180820 (ECOG). C. Duy was supported by an LLS fellow award (LLS 5486) in partnership with The Jake Wetchler Foundation, and is a Forbeck scholar.
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
VL - 11
SP - 1542
EP - 1561
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 6
ER -