ONCOREQUISITE ROLES OF ALDEHYDE DEHYDROGENASE 1A2 IN THE MOLECULAR PATHOGENESIS OF T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

Abstract

ALDH1A2, one of aldehyde dehydrogenases family genes, is ectopically overexpressed in T-cell acute lymphoblastic leukemia (T-ALL). However, its molecular functions in T-ALL pathogenesis are poorly understood. In this thesis, I demonstrated that the oncogenic TAL1 transcriptional complex binds to an intragenic regulatory element of ALDH1A2 and aberrantly activates the alternative promoter of the short isoform, which is specific to T-ALL cells. The short isoform still retains enzymatic activity in catalyzing the oxidation of aldehydes. Importantly, ALDH1A2 promotes the viability and survival of T-ALL cells. Unbiased gene expression and metabolome profiling demonstrated that ALDH1A2 promotes glycolysis and mitochondria respiration, thereby supporting energy production. Additionally, expression of the short ALDH1A2 attenuated the amount of reactive oxygen species (ROS) both in vitro and in vivo. Furthermore, forced expression of short ALDH1A2 in T-cells increased overall penetrance of T-cell malignancy induced by the AKT2 oncogene in a zebrafish model. Taken together, my thesis suggests that ALDH1A2 serves as a requisite to maintain the hyperproliferative state of T-ALL cells (“onco-requisite”).