# Intrinsic and Extrinsic Factors Contributing to Trisomy 21 Preleukemia

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $426,919

## Abstract

PROJECT SUMMARY
 The initiating genetic alterations leading to blood malignancy occur as early as during fetal development.
This is also true in children with Down syndrome (trisomy 21, T21), who have a significantly increased risk of
developing preleukemia and leukemia during early childhood. The vision of our project is to identify and
characterize fundamental mechanisms that contribute towards the initiation of preleukemia in Down syndrome
children and to establish early therapeutic interventions.
 Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia during
childhood compared to children without Down syndrome. In 30% of newborns with Down syndrome, a transient
abnormal myelopoiesis (TAM) occurs, which is characterized by a clonal proliferation of immature
megakaryoblasts that carry somatic mutations in the transcription factor GATA1. The preleukemic state resolves
spontaneously in most newborns but can lead to liver fibrosis and in some cases liver failure. Recently, we
utilized CRISPR/Cas9 editing in human primary fetal liver derived T21 and disomic hematopoietic stem cells
(HSCs) to generate an in vivo model of Down syndrome preleukemia and identified the cellular origin of TAM.
However, it remains unclear how an extra copy of chromosome 21 predisposes HSCs to blood malignancy, why
somatic mutations are acquired with high frequency and what factors cooperate with GATA1 to initiate TAM.
Because the liver is the primary site of hematopoiesis during fetal development, we hypothesize that a
combination of intrinsic and extrinsic factors related to T21 and the fetal liver microenvironment contributes to
the higher susceptibility towards preleukemia development.
 The overall objective of our project is to define specific mechanisms that explain the underlying
predisposition of T21 fetal liver HSCs towards initiating preleukemia. In Aim 1, we are proposing to characterize
intrinsic factors in T21 HSCs from fetal liver through mapping the gene expression and mutational burden at
single cell resolution. We will assess transcriptional differences in the development and lineages of T21 HSCs
compared to disomic fetal liver. In addition, we will quantify the rate of somatic mutations in each subpopulation.
In Aim 2, we plan to characterize extrinsic factors in the T21 fetal liver microenvironment through transcriptional
and spatial profiling of the fetal liver. We will carry out functional studies to assess the interaction of stromal
components with T21 HSCs. Finally, in Aim 3, we are proposing to functionally evaluate the roles of candidate
pathways in preleukemia initiation using our previously established model and primary TAM patient samples.
Our goal is to identify and characterize therapeutic targets for preleukemia and associated liver fibrosis.
 The proposed research has the potential to change our basic understanding of why Down syndrome
children are susceptible to preleukemia and our results could provide a ...

## Key facts

- **NIH application ID:** 10881062
- **Project number:** 1R01CA290681-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Elvin Wagenblast
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $426,919
- **Award type:** 1
- **Project period:** 2024-05-03 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881062

## Citation

> US National Institutes of Health, RePORTER application 10881062, Intrinsic and Extrinsic Factors Contributing to Trisomy 21 Preleukemia (1R01CA290681-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10881062. Licensed CC0.

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