HSPCs with high JAK-STAT signaling, integrated stress response and mitochondrial respiration are particularly sensitive to tamoxifen-induced cell death.
Tamoxifen derivatives accumulate in the mitochondria, where they bind to and inhibit complex I. Biochemical complex I inhibition adds to reduced complex I gene transcription after tamoxifen treatment. Additionally, tamoxifen further increases integrated stress response in HSPCs and tips the balance from protective (p-eIF2α-dependent) to proapoptotic (ATF4-mediated) unfolded protein response. Through transcriptional regulation and previously unrecognized direct metabolic effects, tamoxifen can eliminate cells with pathogenic JAK-STAT activation by modulating integrated sress response and inhibiting mitochondrial complex-I and ATP generation, preventing pathogenic STAT5 phosphorylation.