CD34+ AML cells with low mitochondrial activity show increased expression of stemness-genes and can be targeted by the BCL-2 inhibitor Venetoclax

It has been shown that AML cells with low levels of reactive oxygen species (ROS) have characteristics of LSCs as defined by in vitro and in vivo experiments. We investigated how distinct ROS levels within the stem cell enriched AML CD34+ cell fraction correlate with cellular functions and characteristics such as morphology, metabolic activity, gene expression and drug responsiveness. The results demonstrate that CD34+ AML cells with low ROS levels corresponded with the CD34+/CD38- AML subfraction and showed significantly increased expression of stemness-associated genes and negative regulators of signaling and had a lower mitochondrial number and activity. Moreover, CD34+ AML cells with low ROS levels could be efficiently targeted with the BCL-2 inhibitor Venetoclax despite their similar BCL-2 expression levels compared to the less sensitive CD34+ AML fraction with high ROS levels. RNA sequencing of primary AML samples sorted for ROSlow and ROShigh