# Regulation of hematopoiesis by CUX1

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2020 · $399,048

## Abstract

PROJECT SUMMARY
Myelodysplastic syndromes (MDS) are disorders of hematopoietic stem and progenitor cells (HSPCs) that
results in cytopenias, however, the genetic causes of this dysfunctional hematopoiesis remain unclear. Almost
all patients suffer anemia, a major cause of morbidity, mortality, and health care costs. Deletion of part or all of
chromosome 7 [-7/del(7q)] is a common cytogenetic abnormality in MDS and carries a poor prognosis. We
identified CUX1, a homeodomain-containing transcription factor encoded on 7q, to be frequently inactivated in
myeloid diseases. We reported that CUX1 has highly conserved regulatory functions in both human and
Drosophila blood cells. CUX1 inactivating mutations have since been reported in MDS and are independently
associated with a poor prognosis. We have now generated an innovative Cux1 knockdown mouse model.
Cux1-knockdown mice develop a spontaneous myeloproliferative disorder with many features of human MDS,
including megakaryocyte, granulocyte, and erythroid dysplasia, and a fatal anemia. Preliminary studies
indicate that Cux1 knockdown impacts multiple stages of hematopoiesis, disrupting early HSPC functions as
well as blocking late stages of erythroid development. A major knowledge gap, which this proposal is designed
to address, is the mechanism by which CUX1 regulates normal hematopoiesis. The overall objective is to
determine the transcriptional role for CUX1 in normal HSPCs and erythroid progenitors and the pathways
downstream of CUX1 haploinsufficiency that block erythroid differentiation. Aim 1: Hypothesis – CUX1 is a
transcriptional regulator of HSPC homeostasis conserved in mice and humans. We will take advantage of our
novel mouse model for in vivo analyses of Cux1 regulation of HSPC quiescence, proliferation, and
differentiation. We will perform complementary studies with primary human HSPCs to establish the
translational relevance of this work. We will capitalize on leading-edge functional genomics approaches to
identify CUX1 genomic targets in human HSPCs. Aim 2: Hypothesis – CUX1 promotes erythroblast cell cycle
exit necessary for terminal differentiation by repressing PI3K signaling. We will identify the specific
developmental stage of erythropoiesis disrupted by Cux1 knockdown in mice. We will determine the
conserved role for CUX1 in human red cell development, and the pathways induced by CUX1 deficiency that
disrupt erythropoiesis. Our functional and genomic analyses of primary human HSCs will dovetail with in vivo
assays to elucidate the critical role for CUX1 transcriptional regulation of normal erythropoiesis. This work will
have a positive impact on the fields of HSC and erythroid biology by identifying the molecular mechanism by
which CUX1 regulates normal HSC functions and the pathogenesis of CUX1-deficiency in disease states. Our
studies will reveal novel therapeutic targets for treating anemia in MDS patients and a murine model of MDS
for preclinical studies.

## Key facts

- **NIH application ID:** 9948746
- **Project number:** 5R01HL142782-03
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Megan McNerney
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $399,048
- **Award type:** 5
- **Project period:** 2018-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948746

## Citation

> US National Institutes of Health, RePORTER application 9948746, Regulation of hematopoiesis by CUX1 (5R01HL142782-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9948746. Licensed CC0.

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