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Roles of ALDH in T-ALL
has also been reported in the Myc-induced zebrafish T- ALL model.46 However, hypermetabolic and hyperprolif- erative states often induce ROS production through the upregulation of mitochondrial bioenergetics. Hence, malignant cells may need to balance the ROS level depending on their state of proliferation. Thus, ALDH1A2 expression may be ideal for leukemic or pre- leukemic clones to protect cells from ROS production and further promote metabolism (Figure 8).
Genetic abnormalities in T-ALL can be classified into “type A” and “type B” abnormalities. The former refer to abnormal expression of transcription factor genes, such as TAL1, that delineate distinct molecular pathways, which are more prevalent in one subgroup than others.4,47-49 The latter refer to oncogenic pathways that are commonly observed across different subgroups of T-ALL, for exam- ple, PI3K-AKT and NOTCH1-MYC.2,48,49 Considering the high occurrence of ALDH1A2 expression with PI3K-AKT and NOTCH1-MYC abnormalities in the TAL1-positive subgroup, these pathways may compensate for each other and synergize, which would lead to further increas- es in cell proliferation and metabolism. ALDH1A2 expres- sion may be advantageous as a preceding event that serves as a “requisite” before the cells activate other onco- genic pathways, making it an “oncorequisite”.
Contributions
CZ, SA, CW, MZA, WZL and SHT performed the experi- ments; ZL and AEJY provided primary samples; TKT and LMN performed the computational analysis; SK advised on the metabolome analysis; CZ and TS designed the research and wrote the paper.
Acknowledgments
We thank Nature Publishing Group Language Editing for editing the manuscript. We thank members of the Sanda labo- ratory for discussions, and Motomi Osato, Michelle Mok, Akiko Nambu and Lee Shuying for technical advice. The results pub- lished here are in whole or part based upon data generated by the Therapeutically Applicable Research to Generate Effective Treatments (https://ocg.cancer.gov/programs/target) initiative, phs000218. The data used for this analysis are available at https://portal.gdc.cancer.gov/projects.
Funding
The research was supported by the National Research Foundation (NRF) Singapore and the Singapore Ministry of Education (MOE) under its Research Centers of Excellence initia- tive. The research was also supported by the NRF under its Competitive Research Programme (NRF-NRFF2013-02) and the RNA Biology Center at CSI Singapore, NUS, from funding by the Singapore MOE’s Tier 3 grants (MOE2014-T3-1-006). AEJY is supported by the National Medical Research Council, Singapore (NMRC/CSA/0053/2013 and MOH-CSASI18may-0004).
Disclosures
No conflicts of interest to disclose.
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