Oncogenic DHX15 mutation enhances mitochondrial metabolism and sustains leukemia stemness.
The study reports that DHX15 R222G is associated with inferior prognosis in pediatric RUNX1::RUNX1T1-positive AML, promotes leukemia stem-cell activity and chemotherapy resistance through TFAM-linked oxidative phosphorylation, and creates preclinical sensitivity to the Complex V inhibitor S-Gboxin.
Open original publication →What the AI sees
The study reports that DHX15 R222G is associated with inferior prognosis in pediatric RUNX1::RUNX1T1-positive AML, promotes leukemia stem-cell activity and chemotherapy resistance through TFAM-linked oxidative phosphorylation, and creates preclinical sensitivity to the Complex V inhibitor S-Gboxin.
Research significance
The supplied evidence supports DHX15 R222G as a candidate risk biomarker and shows anti-leukemic activity of OXPHOS inhibition in the studied leukemia setting; it remains an inference, requiring prospective validation and human testing, that patients with RUNX1::RUNX1T1-positive, DHX15-mutant AML would benefit from an OXPHOS inhibitor or its combination with chemotherapy.
Source abstract
The RUNX1::RUNX1T1 translocation, also termed AML1-ETO, is one of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML) and is associated with variable clinical outcomes. The R222G hotspot mutation, located in the RNA helicase gene DHX15, is enriched and predominantly found in AML with this translocation, but its diagnostic significance and underlying mechanism remain largely unclear. In this study, we show that pediatric AML patients carrying DHX15 mutations exhibit an inferior prognosis. Functional analysis demonstrates that DHX15R222G cooperates with AML1-ETO fusion protein to enhance AML leukemia stem cell (LSC) activity and promote resistance to standard chemotherapy. Mechanistically, AML1-ETO transcriptionally upregulates mitochondrial transcription factor A (TFAM), while DHX15R222G promotes TFAM protein stabilization and nuclear translocation, resulting in robust activation of oxidative phosphorylation (OXPHOS) gene expression and mitochondrial respiration. Inhibition of oxidative phosphorylation by the Complex V inhibitor S-Gboxin exerts strong anti-leukemic effects and efficiently circumvents chemotherapy resistance in AML1-ETO+ DHX15R222G leukemia. These findings underscore the pivotal role of oncogenic DHX15 mutations in regulating AML LSC activity and identify DHX15R222G as a potential genetic biomarker for AML risk stratification. Moreover, this mutation may predict therapeutic vulnerability to OXPHOS inhibition.