Leiomyomas disrupt uterine function and cause recurrent pregnancy loss, excessive uterine bleeding, and anemia in 15-30% of reproductive-age women. There are few medical treatments available for leiomyomas, and many women opt to undergo hysterectomy. Understanding how leiomyomas develop is essential for identifying new non-surgical treatments. Preliminary data suggest that the clonal expansion of a defined stem/progenitor cell population is responsible for leiomyoma growth. Employing antibody-based sorting and in vivo tumor reconstruction, we revealed 3 distinct cell populations within a leiomyoma: 1-tumor progenitor CD34+/CD49b+ cells (5%) with self-renewing capacity, which express stem cell markers and the cytokine receptor RANK but are deficient in estrogen and progesterone (E+P) receptors (ER?/PR); 2-intermediately differentiated CD34+/CD49b- ?support? cells (7%) with lower tumorigenicity and high levels of ER?/PR and the cytokine RANKL; and 3-fully differentiated CD34-/CD49b- cells (88%) with negligible tumorigenic potential and high ER?/PR levels. Only the CD34+/CD49b+ cell population was indispensable for robust tumor formation in response to E+P in vivo. These cells, however, are ER?/PR deficient, suggestive of a paracrine mechanism. Our long-range objective is to define the molecular interactions between distinct uterine leiomyoma cell populations that are responsible for self-renewal, proliferation, and E+P responsiveness. The overall hypothesis is that a small stem cell population, devoid of ER? or PR, is essential for E+P-dependent growth, and that steroid-initiated alterations in ER?/PR-expressing support cells are transduced to the stem cells by RANKL/RANK signals. Microarray expression analysis suggested a hierarchical differentiation pattern: CD34+/CD49b+? CD34+/CD49b-? CD34-/CD49b- and multiple paracrine interactions between the CD34+/CD49b+ and CD34+/CD49b- populations, with the latter acting as support cells. E+P induced RANKL expression by over 100-fold in leiomyoma tissue. RANKL induced Cyclin D1 and BCL2 expression and expanded the CD34+/CD49b+ stem cell population. RANKL also activated ERK and NF?B in leiomyoma cells. Using xenografts of sorted leiomyoma cell populations under the mouse kidney capsule and cultures of tissue explants, we will test our hypothesis in vivo and in vitro in the following Aims: 1-Determine whether a small but distinct leiomyoma stem cell population serves as tumor progenitors. We will test the hypothesis that CD34+/CD49b+ cells are responsible for self-renewal, proliferation and robust tumor growth. 2-Define the biological roles of the RANKL/RANK pathway in leiomyoma progenitor/stem cell function. We will test the hypothesis that RANKL/RANK signaling acts in response to E+P and mediates self-renewal and proliferation of CD34+/CD49b+ tumor-initiating cells. In summary, our work will shift the therapeutic focus from the total leiomyoma cell mass to a small stem cell population and paracrine signaling. We expect to identify new therapeutic targets to help prevent tumorigenesis and reduce leiomyoma size and associated symptoms.

Public Health Relevance

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Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD057877-08
Application #
9351188
Study Section
Special Emphasis Panel (ZHD1)
Project Start
2009-08-15
Project End
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Zhang, Qing; Poropatich, Kate; Ubago, Julianne et al. (2018) Fumarate Hydratase Mutations and Alterations in Leiomyoma With Bizarre Nuclei. Int J Gynecol Pathol 37:421-430
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Ikhena, Deborah E; Bulun, Serdar E (2018) Literature Review on the Role of Uterine Fibroids in Endometrial Function. Reprod Sci 25:635-643
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Xie, Jia; Xu, Xiuhua; Yin, Ping et al. (2018) Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma. Lab Invest 98:1575-1587
Xie, Jia; Ubango, Julianne; Ban, Yanli et al. (2018) Comparative analysis of AKT and the related biomarkers in uterine leiomyomas with MED12, HMGA2, and FH mutations. Genes Chromosomes Cancer 57:485-494
Park, Min Ju; Shen, Hailian; Spaeth, Jason M et al. (2018) Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19. J Biol Chem 293:4870-4882
Liu, Shimeng; Yin, Ping; Kujawa, Stacy A et al. (2018) Progesterone receptor integrates the effects of mutated MED12 and altered DNA methylation to stimulate RANKL expression and stem cell proliferation in uterine leiomyoma. Oncogene :

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