# Function of RUNX1 in diverse Down syndrome tissues

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2023 · $191,486

## Abstract

Project Summary
Parent Proposal: RUNX1, also known as Acute Myeloid Leukemia 1 protein (AML1), is a
transcription factor that plays a critical function in the specification of the hematopoietic lineage
during embryogenesis and is required for normal megakaryopoiesis throughout the postnatal
life. The RUNX1 gene is localized to band q22.12 of chromosome 21, which is triplicated in
individuals with Trisomy 21 (T21). For this reason, an extra copy of RUNX1 has been proposed
to play relevant roles in the hematological alterations associated with Down syndrome (DS). We
seek to decipher the contribution of RUNX1 to the phenotypes seen in individuals with Down
syndrome. Since transcription factors bind to DNA and alter RNA polymerase activity, we will
determine if those two functions of RUNX1 are altered in Down syndrome-derived cells. We will
also define if drugs that increase or inhibit RUNX1 function behave differently in cells with an
extra copy of chromosome 21. Finally, we will ascertain how much of the altered blood
differentiation seen in Down syndrome is caused by RUNX1 by ‘normalizing’ RUNX1 gene
dosage in a trisomy background (e.g., two copies in a trisomy cell line). We will then analyze the
differentiation of iPSCs into embryoid bodies and blood cells. Collectively this work will shed
important insights into the functions of RUNX1 and how it is altered in Trisomy 21.
Supplement Project Summary: A recent report by Gialesaki et al. (March 2023) established a
critical role for RUNX1 alternative splicing and isoform imbalance -rather than overall
expression- as a major driver of Down syndrome-associated myeloid leukemia (DS-ML). These
findings have important implications on most of the specific aims of our proposal. Therefore, we
should partially modify some of our sub-aims to assess the relevance of RUNX1 splicing
equilibrium on the different outcomes of DS-derived iPSC and lymphoblastoid cell differentiation
and homeostasis. A second motivation for this supplement applies exclusively to Aim 3. Here
we orginally proposed to normalize RUNX1 gene dosage by knocking-out one copy in the T21
+/+/−
iPSC line (T21 RUNX1 ). We now propose alternative strategies to overcome such
obstacles and incorporate the isoform-specific analyses just mentioned. This Administrative
Supplement addresses Component 1: A targeted high risk - high reward basic science study
that is relevant to Leukemia risk in Down syndrome. Moreover this supplement will significantly
improve the scientific significance of the project by contributing to a better understanding of the
underlying mechanisms that govern hematological alterations in individuals with T21.

## Key facts

- **NIH application ID:** 10853906
- **Project number:** 3R01HL156475-01S1
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Mary A Allen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $191,486
- **Award type:** 3
- **Project period:** 2023-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853906

## Citation

> US National Institutes of Health, RePORTER application 10853906, Function of RUNX1 in diverse Down syndrome tissues (3R01HL156475-01S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10853906. Licensed CC0.

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