Targeting DDX3X eliminates leukemia stem cells in chronic myeloid leukemia by blocking NT5DC2 mRNA translation.

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.