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Acute Lymphoblastic Leukemia
Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis
of T-cell acute lymphoblastic leukemia
Ferrata Storti Foundation
Haematologica 2021 Volume 106(6):1545-1558
Chujing Zhang,1 Stella Amanda,1 Cheng Wang,2 Tze King Tan,1 Muhammad Zulfaqar Ali,1 Wei Zhong Leong,1 Ley Moy Ng,1 Shojiro Kitajima,3 Zhenhua Li,4 Allen Eng Juh Yeoh,1,4 Shi Hao Tan1 and Takaomi Sanda1,5
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; 4VIVA-NUS CenTRAL, Department of Pediatrics, National University of Singapore, Singapore and 5Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
ABSTRACT
Aldehyde dehydrogenases (ALDH) are overexpressed in various types of cancers. One of the ALDH family genes, ALDH1A2, is aberrantly expressed in more than 50% of cases of T-cell acute lymphoblastic leukemia (T-ALL). However, its molecular function and role in the pathogenesis of T-ALL are largely unknown. Chromatin immunoprecipitation-sequencing and RNA-sequencing 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 tricarboxylic acid cycle, accompanied by NADH production, by affecting multiple meta- bolic enzymes to promote ATP production. Depletion of ALDH1A2 increased the levels of reactive oxygen species, while the 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 model of T-ALL. 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.
Introduction
T-cell acute lymphoblastic leukemia (T-ALL) is a hematologic malignancy that arises from immature T-cell precursors.1,2 This type of leukemia occurs mostly in children but is also found in adults. A number of chromosomal and genetic abnor- malities have been identified in T-ALL, many of which affect genes encoding tran- scription factors.3 Gene expression and mutational profiles have demonstrated that T-ALL cases can be classified into mutually exclusive subgroups based on the expression of several transcription factors (TAL1, TAL2, LYL1, LMO1, LMO2, TLX1/HOX11, TLX3/HOX11L2, HOXA and NKX3-1).4-6 This suggests that each transcription factor drives a distinct cellular program that may work in concert with other molecular pathways in T-ALL cells.
TAL1-positive T-ALL constitutes the largest subgroup, accounting for 40-60% of all primary cases.4,7-11 One of the known downstream targets of TAL1 in T-ALL cells is ALDH1A2,12,13 a member of the aldehyde dehydrogenase (ALDH) family of genes that encode oxidoreductases. ALDH proteins convert a variety of aldehydes into carboxylic acids.14,15 They detoxify endogenous aldehydes, generated during the
Correspondence:
TAKAOMI SANDA
takaomi_sanda@nus.edu.sg
Received: December18,2019. Accepted: May 14, 2020. Pre-published: May 15, 2020.
https://doi.org/10.3324/haematol.2019.245639
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