Authors: Cihangir Duy, Meng Li, Matt Teater, Cem Meydan, Francine E Garrett-Bakelman, Tak C. Lee, Christopher R Chin, Ceyda Durmaz, Kimihito C. Kawabata, Eugen Dhimolea, Constantine S. Mitsiades, Hartmut Doehner, Richard J. D'Andrea, Michael W Becker, Elisabeth M. Paietta, Christopher E Mason, Martin Carroll, Ari M Melnick
Summary: 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.
Source: Cancer Discovery, 2021; candisc.1375.2020