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

Azna Zuberi, Yongchao Huang, Ariel J. Dotts, Helen Wei, John S. Coon, Shimeng Liu, Takashi Iizuka, Olívia Wu, Olivia Sotos, Priyanka Saini, Debabrata Chakravarti, Thomas G. Boyer, Yang Dai, Serdar E. Bulun, Ping Yin
In: JCI Insight · 2023 · vol. 8(18) · doi:10.1172/jci.insight.171305 · PMID:37607000 · W4386046500
article OA: gold CC0 ⤵ 2 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-10 ⓘ

MED12 mutations in uterine leiomyomas activate the tryptophan/kynurenine/AHR pathway, promoting tumor growth and progesterone receptor regulation of AHR signaling.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 ⓘ

This study investigated how MED12 mutations modulate metabolic signaling in uterine leiomyomas, using cell and molecular approaches to examine the tryptophan/kynurenine/AHR pathway. The authors report that MED12 mutation–driven activation of the tryptophan/kynurenine/AHR axis promotes leiomyoma growth through pathway-dependent changes in downstream gene expression and proliferative behavior. A major caveat is that the work focuses on mechanistic pathway effects in leiomyoma models rather than providing direct clinical outcome validation. Relevance to endometriosis: the paper is included in this corpus due to its study of uterine hormone-related tumor growth pathways in reproductive tract diseases, though it does not specifically center endometriosis or adenomyosis.

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Abstract

Uterine leiomyomas cause heavy menstrual bleeding, anemia, and pregnancy loss in millions of women worldwide. Driver mutations in the transcriptional mediator complex subunit 12 (MED12) gene in uterine myometrial cells initiate 70% of leiomyomas that grow in a progesterone-dependent manner. We showed a distinct chromatin occupancy landscape of MED12 in mutant MED12 (mut-MED12) versus WT-MED12 leiomyomas. Integration of cistromic and transcriptomics data identified tryptophan 2,3-dioxygenase (TDO2) as the top mut-MED12 target gene that was significantly upregulated in mut-MED12 leiomyomas when compared with adjacent myometrium and WT-MED12 leiomyomas. TDO2 catalyzes the conversion of tryptophan to kynurenine, an aryl hydrocarbon receptor (AHR) ligand that we confirmed to be significantly elevated in mut-MED12 leiomyomas. 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 receptors 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 leiomyomas promoted tumor growth and may inform the future development of targeted treatments and precision medicine.

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last seen: 2026-06-10T17:14:06.276822+00:00
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