Related Experiment Video
Updated: Jun 8, 2025
Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
Published on: January 7, 2019
Targeting DDX3X eliminates leukemia stem cells in chronic myeloid leukemia by blocking NT5DC2 mRNA translation
Chen Duan1,2, Xiaoying Lin1,2, Waiyi Zou3
1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China.
Abstract:
Tyrosine kinase inhibitors (TKIs) are highly effective in the treatment of patients with chronic myeloid leukemia (CML), but fail to eliminate leukemia stem cells (LSCs), which can lead to disease relapse or progression. It is urgently need to identify the regulators specifically driving LSCs. In this study, we identified DEAD-box helicase 3 X-linked (DDX3X), a ubiquitously expressed RNA helicase, as a critical regulator for CML LSCs by using patient samples and BCR-ABL-driven CML mouse model. We found that DDX3X enhanced the survival, serially plating and long-term engraftment abilities of human primary CML CD34+ cells. Inhibition of DDX3X reduced leukemia burden, eradicated LSCs and extended the survival of CML mice. Mechanistically, we uncovered that DDX3X protein bound to 5'-Nucleotidase Domain Containing 2 (NT5DC2) mRNA and promoted its translation in CML cells. NT5DC2 was a functional mediator in DDX3X regulation of LSCs. Collectively, our findings provide new evidence for RNA helicase facilitating the translation of specific mRNA in LSCs. Targeting DDX3X may represent a promising therapeutic strategy for eradication of LSCs in CML patients.
Insights
Targeting DEAD-box helicase 3 X-linked (DDX3X) may eradicate leukemia stem cells (LSCs) in chronic myeloid leukemia (CML). This RNA helicase drives LSC survival and engraftment, and its inhibition reduces leukemia burden and improves survival in CML models.
Area of Science:
- Hematology
- Molecular Biology
- Cancer Research
Background:
- Tyrosine kinase inhibitors (TKIs) are effective for chronic myeloid leukemia (CML) but do not eliminate leukemia stem cells (LSCs).
- LSCs are responsible for disease relapse and progression in CML.
- Identifying regulators specific to LSCs is crucial for developing curative therapies.
Purpose of the Study:
- To identify critical regulators driving leukemia stem cells (LSCs) in chronic myeloid leukemia (CML).
- To investigate the role of DEAD-box helicase 3 X-linked (DDX3X) in CML LSC biology.
- To explore DDX3X as a potential therapeutic target for CML eradication.
Main Methods:
- Utilized patient samples and a BCR-ABL-driven CML mouse model.
- Assessed the impact of DDX3X inhibition on CML cell survival, serial plating, and engraftment.
- Investigated the molecular mechanism by examining DDX3X interaction with 5'-Nucleotidase Domain Containing 2 (NT5DC2) mRNA.
Main Results:
- DEAD-box helicase 3 X-linked (DDX3X) was identified as a critical regulator of CML LSCs.
- DDX3X enhances the survival, serial plating, and long-term engraftment of CML CD34+ cells.
- Inhibition of DDX3X reduced leukemia burden, eradicated LSCs, and prolonged survival in CML mice.
- DDX3X promotes the translation of 5'-Nucleotidase Domain Containing 2 (NT5DC2) mRNA, which mediates its effects on LSCs.
Conclusions:
- DDX3X plays a key role in maintaining CML LSCs.
- Targeting DDX3X offers a promising therapeutic strategy for eradicating CML LSCs.
- This study highlights the importance of RNA helicases in regulating specific mRNA translation within LSCs.
