# Defining LncRNA Function in normal and Shwachman Diamond Syndrome Myelopoiesis

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2022 · $441,250

## Abstract

Project Summary
Shwachman-Diamond Syndrome (SDS) is an inherited bone marrow failure syndrome affecting multiple organ
systems. However, the hematological defects in SDS remain poorly characterized. We used single cell RNA
sequencing to identify increased TGF signaling specifically in hematopoietic stem cells (HSCs) and
multipotent progenitors (MPPs), but not lineage-committed progenitors. We also identified significantly reduced
expression of lncRNAs that normally down-regulate TGF signaling. Our data implicate lncRNAs in SDS bone
marrow failure.
To define how lncRNAs function in normal myelopoiesis and how their dysregulation is pathogenic in SDS, we
will use a recently developed yeast three hybrid (Y3H) assay to systematically define lncRNA-protein
interactions for 100 lncRNAs identified in normal and disease hematopoiesis. Y3H is capable of detecting low-
abundance and low-affinity interactions lncRNA-protein interactions. Overlaying the lncRNA-protein interacting
onto existing PPI networks will define lncRNA-regulated pathways of normal myelopoiesis and their
dysregulation in SDS. Because we will screen of overlapping lncRNA fragments of 100 individual lncRNAs,
these studies will enable systematic lncRNA structure-function analyses. The information obtained through this
structure-function analysis will be critical for establishing sequence and/or structural parameters which may
enable prediction of lncRNA-protein binding activity, thereby advancing our understanding of the biology of
lncRNAs, even those not included in this initial screen.
We will then validate roles for lncRNAs in hematopoiesis and altered TGF activation. Specifically, we will use
CD34+ cells depleted of SBDS and increase (by ectopic expression) or decrease (by knockdown) lncRNAs
and their interacting proteins and test these effects in self renewal, myeloid lineage commitment, proliferation,
cell death, oxidative stress, inflammation and TGF activation. To further test roles for specific lncRNAs in
TGF signaling, we will also test the ability of TGF inhibitors to rescue normal hematopoietic function. We will
identify TGF-responsive genes in affected subpopulations that could be targeted for novel SDS therapies, and
test their function in SDS hematopoiesis. Thus, these studies will (1) identify lncRNAs, proteins, and lncRNA-
protein interactions directing normal and SDS pathogenic myeloid function; (2) develop a platform for
systemically studying lncRNAs; and (3) provide pre-clinical evidence that could support a clinical trial targeting
lncRNA-directed pathways for future SDS therapy.

## Key facts

- **NIH application ID:** 10320386
- **Project number:** 5R01HL145714-04
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** CARL D NOVINA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $441,250
- **Award type:** 5
- **Project period:** 2019-01-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320386

## Citation

> US National Institutes of Health, RePORTER application 10320386, Defining LncRNA Function in normal and Shwachman Diamond Syndrome Myelopoiesis (5R01HL145714-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10320386. Licensed CC0.

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