MED12 mutation activates the tryptophan/kynurenine/AHR pathway to promote growth of uterine leiomyomas

Uterine leiomyomas cause heavy menstrual bleeding, anemia, and pregnancy loss in approximately 10 million US women. Driver mutations in the transcriptional mediator complex subunit 12 (MED12) gene in uterine myometrial cells initiate 70% of leiomyoma that grow in a progesterone-dependent manner. We showed a distinct chromatin occupancy landscape of MED12 in mutant (mut)- vs wild-type (wt)-MED12 leiomyoma. Integration of cistromic and transcriptomic data identified tryptophan 2,3-dioxygenase (TDO2) as the top mut-MED12 target gene, which was significantly upregulated in mut-MED12 leiomyoma when compared to adjacent myometrium and wt-MED12 leiomyoma. TDO2 catalyzes the conversion of tryptophan to kynurenine, an aryl hydrocarbon receptor (AHR) ligand that we confirmed to be significantly elevated in mut-MED12 leiomyoma. Treatment of primary mut-MED12 leiomyoma cells with tryptophan or kynurenine stimulated AHR nuclear translocation, increased proliferation, inhibited apoptosis, and induced AHR-target gene expression, whereas blocking the TDO2-kynurenine-AHR pathway by siRNA or pharmacological treatment abolished these effects. Progesterone receptor regulated the expression of AHR and its target genes. In vivo, TDO2 expression positively correlated with the expression of genes crucial for leiomyoma growth. In summary, activation of the TDO2-kynurenine-AHR pathway selectively in mut-MED12 leiomyoma promotes tumor growth and may inform the future development of targeted treatments and precision medicine.