NHE1 sustains leukemia-propagating capacity and mitochondrial fitness in T-cell acute lymphoblastic leukemia

The authors screened 786 FDA-approved compounds in a zebrafish transplantation model and found that amiloride markedly reduced leukemia-initiating cell frequency in T-ALL without clearly delaying disease onset. Mechanistically, NHE1 knockdown reduced colony formation by T-ALL cells by more than 70%; transcriptomic and proteomic analyses showed decreased abundance of proteins involved in mitochondrial respiration and translation, and metabolomics revealed altered TCA cycle intermediates. In mouse xenografts, leukemia involvement in bone marrow and spleen was reduced, but overall survival did not differ significantly.