Chemotherapy-induced cellular senescence suppresses progression of Notch-driven T-ALL

Abstract

T cell acute lymphoblastic leukemia (T-ALL) is a serious hematologic malignancy that occurs in children and young adults. Current therapies include intensive chemotherapy and ionizing radiation that preferentially kill malignant cells. Unfortunately, they are frequently accompanied by unintended negative impacts, including the induction of cellular senescence and long-term toxicities in normal host tissues. Whether these senescent cells resulting from therapy increase the susceptibility to relapse or secondary cancers is unknown. Using transgenic and pharmacological approaches to eliminate doxorubicin-induced senescent cells in a Notch-driven T-ALL relapse mouse model, we find that these cells inhibit tumor recurrence, suggesting that senescence in response to treatment suppresses tumorigenesis. This finding, together with extensive evidence from others demonstrating that ageassociated health problems develop dramatically earlier among childhood cancer survivors compared to age-matched counterparts, suggests a relationship between therapy-induced senescence and tumorigenesis. Although cancer risk is increased through accelerated premature- aging in the long run, therapy-induced senescence appears to protect survivors from recurrence, at least in the short run.