Abstract LB-301: Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia

Abstract

Abstract Aldehyde dehydrogenases (ALDHs) have been implicated as a stem cell marker both in normal and malignant cells. Elevated ALDH activity is associated with the stemness capability as well as the drug resistance in various cancers. As a notable example, ALDH1A2, one of ALDH family genes, is ectopically overexpressed in T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological disease that results from malignant transformation of T-cell progenitors. However, its roles and molecular functions in T-ALL pathogenesis are poorly understood. In our study, we demonstrated that the oncogenic transcription factor TAL1 directly induces an expression of ALDH1A2 in T-ALL cells, while normal T-cells do not express this gene. The 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. Using in vitro enzymatic assay, we found that the short isoform still retain 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, our data suggests that ALDH1A2 is crucial and advantageous for T-ALL cell viability and survival by mediating energy production and by protecting cancer cells from oxidative stresses, thus serving as a requisite to maintain the hyperproliferative state of T-ALL cells (“onco-requisite”). Citation Format: CHUJING ZHANG, Stella Amanda, Cheng Wang, Tze King Tan, Zulfaqar Ali Muhammad, Wei Zhong Leong, Ley Moy Ng, Shojiro Kitajima, Zhenhua Li, Allen Eng Juh Yeoh, Shi Hao Tan, Takaomi Sanda. Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-301.