PUBLICATION
Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia
- Authors
- Zhang, C., Amanda, S., Wang, C., Tan, T.K., Ali, M.Z., Leong, W.Z., Ng, L.M., Kitajima, S., Li, Z., Yeoh, A.E.J., Tan, S.H., Sanda, T.
- ID
- ZDB-PUB-200518-3
- Date
- 2020
- Source
- Haematologica 106(6): 1545-1558 (Journal)
- Registered Authors
- Sanda, Takaomi
- Keywords
- ALDH1A2, Pediatric Acute Lymphoblastic Leukemia, TAL1, metabolism, reactive oxygen species
- MeSH Terms
-
- Aldehyde Dehydrogenase*/genetics
- Animals
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma*/genetics
- T-Cell Acute Lymphocytic Leukemia Protein 1
- T-Lymphocytes
- Transcription Factors
- Zebrafish
- PubMed
- 32414855 Full text @ Haematologica
Citation
Zhang, C., Amanda, S., Wang, C., Tan, T.K., Ali, M.Z., Leong, W.Z., Ng, L.M., Kitajima, S., Li, Z., Yeoh, A.E.J., Tan, S.H., Sanda, T. (2020) Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia. Haematologica. 106(6):1545-1558.
Abstract
Aldehyde dehydrogenases (ALDHs) are overexpressed in various types of cancers. One of the ALDH family genes, ALDH1A2, is aberrantly expressed in more than 50% of T-cell acute lymphoblastic leukemia (T-ALL) cases. However, its molecular function and role in T-ALL pathogenesis are largely unknown. ChIP-seq and RNA-seq analyses showed that the oncogenic transcription factor TAL1 and its regulatory partners bind to the intronic regulatory element of the ALDH1A2 gene, directly inducing a T-ALL-specific isoform with enzymatic activity. ALDH1A2 was preferentially expressed in the TAL1-positive T-ALL subgroup. In T-ALL cell lines, depletion of ALDH1A2 inhibited cell viability and induced apoptosis. Interestingly, gene expression and metabolomic profiling revealed that ALDH1A2 supported glycolysis and the TCA cycle, accompanied by NADH production, by affecting multiple metabolic enzymes to promote ATP production. Depletion of ALDH1A2 increased the levels of reactive oxygen species (ROS), while ROS levels were reduced by ALDH1A2 overexpression both in vitro and in vivo. Overexpression of ALDH1A2 accelerated tumor onset and increased tumor penetrance in a zebrafish T-ALL model. Taken together, our results indicate that ALDH1A2 protects against intracellular stress and promotes T-ALL cell metabolism and survival. ALDH1A2 overexpression enables leukemic clones to sustain a hyper-proliferative state driven by oncogenes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping