T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10-15% of pediatric and 20-25% of adult cases of ALL. The cure rates for patients with T-ALL is approaching 80% in children while falling to 60% in adult cases. These numbers further decline in patients with primary resistance or who relapse from their initial diseases. Given the poor outcomes for patients with T-ALL, there has been growing interest in identifying risk factors that contribute to the pathogenesis of this disease. Recently, obesity (characterized by a body mass index > 30) has been shown to reduce the survival of patients with ALL. However, a closer examination of the epidemiological data revealed that obese patients with T-ALL exhibit significant improvements in survival outcomes. These data prompt several questions including; 1) what are the specific factors in the obese microenvironment that impact the function of T-ALL, 2) how do T-leukemia cells respond to these factors, and 3) are the responses influenced by mutations commonly found in T-ALL. To address these questions, we have studied how stromal cell and adipocyte-secreted factors impact the function of human T-ALL cells. Furthermore, we sought to determine if Notch1, which is mutated in > 60% of T-ALL cases, contribute to how T-leukemia cells respond to soluble factors in the microenvironment. When human T-ALL cells were grown in vitro with RPMI, stromal cell-conditioned media (SCM), or adipocyte-conditioned media (ACM), only ACM exposure resulted in extensive cell death of T-ALL (30-80% after 3 days of culture) which occurred independently of the mutational status of Notch1 and p53. The ACM secreted factor(s) that induced cell death in T-leukemia cells was revealed to be proteinaceous in nature, given that protease treatment of ACM completely abolished ACM-mediated apoptosis in T-ALL. Cell cycle analysis of human T-ALL exposed to ACM revealed an accumulation in the sub G1 population in human T-ALL, confirming the induction of apoptosis induced by the adipocyte secretome. Although the mutation status of Notch did not impact cell death, Notch1 protein levels significantly decreased in T-leukemia cells after 3 days of culture in ACM which coincided with increased γ-H2AX activation (indicative of DNA damage). This observation was confirmed using immunofluorescent microscopy, which revealed co-localization of γ-H2AX and 53BP1 (a p53 binding protein) in ACM-exposed human T-leukemia cells. Furthermore, extensive nuclear membrane blebbing was observed in human T-ALL exposed to ACM, but not SCM or unconditioned-media. Our studies reveal that adipocyte-secreted proteins are cytotoxic to human T-leukemia cells, which is independent of the mutational status of Notch1 and p53. Given this global effect, our results suggest that the obese microenvironments presents a unique opportunity to develop novel therapeutics for treating standard and high-risk patients with T-ALL.
Citation Format: Miyoung Lee, Curtis J. Henry. Adipocyte-secreted proteins induce DNA damage and apoptosis in T-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 505.