# Investigations of menin function in Ewing sarcoma

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $23,829

## Abstract

PROJECT SUMMARY
Pediatric cancers can be considered developmental disorders in which oncogenic drivers hijack normal
developmental programs to promote tumorigenesis. The scaffolding protein menin is essential for normal
development and, in human cancer, can function as a tumor suppressor or an oncogene, depending on
context. The diverse functions of menin are linked to its role in regulation of gene transcription via its
interaction with MLL histone methyltransferases, as well as with other context-dependent binding partners. In
MLL-rearranged leukemia (MLLr), protein:protein interactions between menin and MLL-fusion proteins drive
epigenetic activation of oncogenic transcription programs. A critical dependence of MLLr leukemia on these
interactions represents a unique therapeutic vulnerability and small molecule inhibitors of the menin:MLL
interaction are being developed for leukemia-directed therapy. Ewing sarcomas are mesenchymal tumors of
presumed stem cell (MSC) origin that are driven by EWS/ETS fusions, most commonly EWS/FLI1. EWS/FLI1
initiates sarcomagenesis by hijacking normal MSC differentiation. Importantly, menin plays an essential role in
early mesenchymal development, where it contributes to both lineage commitment and osteoblastic
differentiation. We have shown that menin is over-expressed by Ewing sarcoma relative to MSC and that loss
of menin results in loss of tumorigenicity. However, the mechanisms by which menin exerts its oncogenic
effects in these tumor cells remain unknown. Our preliminary data identified the serine synthesis pathway
(SSP) and other metabolic pathways as downstream targets of menin in Ewing sarcoma. Our data also
suggest that EWS/FLI1 itself contributes to regulation of menin and its control of cell metabolism. These data
collectively support the hypothesis that menin functions as an oncogenic hub in Ewing sarcoma. In this
proposal, we will investigate the mechanisms of menin function and test the innovative hypothesis that
EWS/FLI1 promotes tumorigenesis by hijacking menin-dependent transcriptional regulation. In Aim 1 we will
determine the mechanism by which menin regulates cell metabolism and will elucidate the role of EWS/FLI1 in
this process. In Aim 2 we will define the key metabolites of the SSP that contribute to tumor maintenance in
order to determine why Ewing sarcoma cells are so dependent on this pathway. In Aim 3 will define genome-
wide transcriptional targets of menin in MSC and Ewing sarcoma and how they are impacted by EWS/FLI1.
The proposed studies will advance fundamental knowledge of the biologic underpinnings of Ewing sarcoma
and discover how EWS/FLI1 hijacks normal menin physiology to promote oncogenesis. It is goal that these
insights will provide opportunities to develop novel, and less toxic, menin-directed therapies for Ewing
sarcoma.

## Key facts

- **NIH application ID:** 10056580
- **Project number:** 3R01CA218116-02S1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Elizabeth R Lawlor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $23,829
- **Award type:** 3
- **Project period:** 2018-06-08 → 2020-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10056580

## Citation

> US National Institutes of Health, RePORTER application 10056580, Investigations of menin function in Ewing sarcoma (3R01CA218116-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10056580. Licensed CC0.

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