# The Origin and Cellular Heterogeneity of Uterine Leiomyomas

> **NIH NIH P50** · NORTHWESTERN UNIVERSITY · 2021 · $442,088

## Abstract

Pharmacologic therapies for uterine leiomyomas are hampered by our limited knowledge regarding the
origin and evolution of these tumors, as well as the degree of molecular heterogeneity. Leiomyomas, also
known as fibroids, are the most common benign tumors of uterine smooth muscle cells and are a major
cause of morbidity among American women. Previous studies have suggested that fibroids are
monoclonal in origin. However, histological and cell sorting analyses of leiomyomas have shown cellular
heterogeneity, with presence of fibroblasts in addition to the smooth muscle cells in leiomyoma tumours.
Whole exome approaches from our group and others have identified mutations in the mediator complex
subunit 12 (MED12) in approximately 70% of LM patients, indicating that MED12 mutant cells might give
rise to leiomyomas. We generated a mouse model that showed leiomyoma tumor formation in uteri that
express Med12 mutation. We will utilize our mouse models to begin the study of leiomyoma early origins
and interact with other Projects of this P50 application, to define molecular heterogeneity of leiomyomas
and their relation to the tumor genotype. Our studies will focus to: 1) understand the onset and
progression of Med12 mutation positive leiomyomas, 2) the evolution of genomic instability in uterine
leiomyomas, and 3) understand the relationship between leiomyoma genotype and molecular
heterogeneity that may impact leiomyoma recurrence rates and non-responsiveness to therapy. Our
mouse model and preliminary findings will complement studies of other investigators in this P50
application. We will provide Dr. Bulun's Project 1 with our mouse model and in vivo preliminary data that
Med12 interacts with the progesterone pathway, as well as complement his studies on different human
leiomyoma cell types with our own studies in mice and humans. Dr. Chakravarti's Project 3 will benefit
from our single cell sequencing on MED12 positive, HMGA2 positive, and MED12/HMGA2 negative
leiomyomas and will complement his epigenetic studies on HMGA2 positive leiomyomas. Together, the
studies proposed by us and our collaborators will provide great insights into the pathophysiology of
uterine LM. Our studies will identify origin of Med12 positive leiomyomas, determine if genotype drives
molecular phenotype and cellular heterogeneity, with a goal of driving targeted therapy for leiomyomas.

## Key facts

- **NIH application ID:** 10153843
- **Project number:** 5P50HD098580-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** ALEKSANDAR RAJKOVIC
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $442,088
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153843

## Citation

> US National Institutes of Health, RePORTER application 10153843, The Origin and Cellular Heterogeneity of Uterine Leiomyomas (5P50HD098580-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10153843. Licensed CC0.

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