Disruption of ER–mitochondrial calcium homeostasis underlies the anti-leukemic activity of tamoxifen in myeloid neoplasms
Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor prognosis and limited therapeutic options. The selective estrogen receptor modulator tamoxifen, widely used in breast cancer, has recently been implicated as potential drug in myeloid neoplasms (MN). Yet, the mechanisms underlying its cytotoxicity remain poorly understood, particularly given the absence of expression of its known target, the estrogen receptor, in myeloid cells.
Here, using a large cohort of primary AML samples (n=30) and AML cell lines (n=12), we identify a subset of cases (33.3%) that display marked sensitivity to tamoxifen. In primary AML blasts (CD34+CD117+ cells), tamoxifen significantly reduced viability and mitochondrial membrane potential, while sparing healthy hematopoietic stem and progenitor cells.
To uncover the molecular basis of this selective vulnerability, we generated a biotinylated tamoxifen analog to be able to perform interactome and localization studies. Streptavidin-mediated biotin-tamoxifen pullouts followed by LC-MS/MS identified proteins associated with the endoplasmic reticulum (ER) and mitochondria, including ATP2A2, VDAC1–3, and members of the SLC25A family, which are key mediators of ADP/ATP exchange and Ca²⁺ transfer between these organelles. Functionally, tamoxifen triggered pronounced ER-to-mitochondria Ca²⁺ efflux, inducing mitochondrial stress and reactive oxygen species accumulation in myeloid cells, but not in breast cancer models. In AML, sensitivity to tamoxifen strongly correlated with the magnitude of Ca²⁺ flux across AML cell lines and patient samples, establishing calcium dysregulation as a central driver of its anti-leukemic effect. Together, these findings reveal that tamoxifen exerts cytotoxicity in AML through disruption of ER–mitochondrial Ca²⁺ homeostasis, leading to mitochondrial dysfunction and apoptosis.
This mechanistic insight positions Ca²⁺ flux signatures as a potential marker for patient stratification and supports therapeutic strategies combining tamoxifen with metabolic or redox-targeted agents to improve treatment efficacy in AML.