# Functional characterization of CUX1 regulators for the treatment of myelodysplastic syndromes

> **NIH NIH F32** · UNIVERSITY OF CHICAGO · 2023 · $74,292

## Abstract

PROJECT SUMMARY/ABSTRACT
The myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by cytopenias
and dysplasia in one or more of the myeloid cell lines due to ineffective hematopoiesis. Patients present with
signs and symptoms of anemia, accompanied by infections and bleeding leading to serious morbidity. Loss of
chromosome 7 (-7) or the long-arm of 7 [del(7q)] is commonly seen in high-risk MDS patients. Treatment
options are limited and high-risk patients have less than one-year survival. Cut-like homeobox 1 (CUX1), a
transcription factor encoded in the commonly deleted segment of 7q22, is expressed at haploinsufficient
transcript and protein levels in -7/del(7q) myeloid diseases. Knockdown of CUX1 causes a spontaneous
hematopoietic disorder with many features of human MDS, including erythroid dysplasia, and fatal anemia,
indicating that loss of this single gene is sufficient to cause disease. Remarkably, CUX1 re-expression reverses
MDS in mice, which provides the premise for the current proposal, that restoration of CUX1 is a viable
therapeutic strategy for MDS patients. However, there exists a major gap in our understanding of the
mechanisms by which CUX1 levels are regulated. Preliminary studies indicate that Glycogen synthase kinase-
3 (GSK3) inhibition increases cellular CUX1 protein levels. The central hypothesis is that pharmacological
induction of CUX1 levels will restore hematopoietic stem cell homeostasis and reverse impaired differentiation
in CUX1 deficient myeloid disease models. The central hypothesis will be tested by pursuing two specific aims:
1) define the cellular and molecular mechanisms by which CUX1 levels are regulated, and 2) drive normal
erythroid differentiation of -7/del(7q) myelodysplasia through therapeutic restoration of CUX1. Under the first
aim, GSK3 mediated post-translational regulatory mechanism of CUX1 levels will be determined using site-
directed mutational analysis in immortalized human blood cell lines. Additionally, a genome-wide
CRISPR/Cas9 loss of function screen will be utilized to identify novel regulators of CUX1. For the second aim,
CD34+ human -7/del(7q) MDS cells and CUX1-deficient mouse models will be used to determine the efficacy
of GSK3 isoform selective inhibitors in restoring CUX1 protein and reversing erythroid differentiation defects.
The proposed research is expected to reveal druggable and regulatory pathways of CUX1 to restore its levels
as a way of reversing anemia and dysplasia in -7/del(7q) MDS patients.

## Key facts

- **NIH application ID:** 10544145
- **Project number:** 5F32HL156600-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Madhavi Dushyanthi Senagolage
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $74,292
- **Award type:** 5
- **Project period:** 2021-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10544145

## Citation

> US National Institutes of Health, RePORTER application 10544145, Functional characterization of CUX1 regulators for the treatment of myelodysplastic syndromes (5F32HL156600-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10544145. Licensed CC0.

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