HomeLatest HappeningsOncorequisite Role of an Aldehyde Dehydrogenase in the Pathogenesis of T-cell Acute Lymphoblastic Leukemia. (Haematologica, May 2020)
Oncorequisite Role of an Aldehyde Dehydrogenase in the Pathogenesis of T-cell Acute Lymphoblastic Leukemia. (Haematologica, May 2020)
Chujing Zhang1, Stella Amanda1, Cheng Wang2, Tze King Tan1, Muhammad Zulfaqar Ali1, Wei Zhong Leong1, Ley Moy Ng1, Shojiro Kitajima3, Zhenhua Li4, Allen Eng Juh Yeoh5, Shi Hao Tan1, Takaomi Sanda6
Author Information 1Cancer Science Institute of Singapore, National University of Singapore, Singapore. 2Department of Anatomy, National University of Singapore, Singapore. 3Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan. 4Department of Paediatrics, National University of Singapore, Singapore. 5Dept of Paediatrics, National University of Singapore & Cancer Science Institute of Singapore. 6Cancer Science Institute of Singapore, National University of Singapore, Singapore; email@example.com.
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.