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

• Published in: Cancer discovery Vol. 11; no. 6; p. 1542
• Main Authors: Duy, 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, Melnick, Ari M
• Format: Journal Article
• Language: English
• Published: United States 01-06-2021
• Subjects: Animals; Cell Line, Tumor - cytology; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - pathology; Mice; Mice, Inbred NOD; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - pathology; Neoplastic Stem Cells - cytology; Phenotype; Remission Induction
• ISSN: 2159-8290
• DOI: 10.1158/2159-8290.CD-20-1375

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.
.