# Cellular and functional impact of SAMD9L mutations on hematopoiesis and myelodysplasia

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2021 · $448,750

## Abstract

PROJECT SUMMARY:
The development of a myelodysplastic syndrome (MDS) is a multistep process involving disease initiation,
clonal progression with acquisition of cooperating mutations and a complex interplay with the
microenvironment. In this proposal, we will focus specifically on the initial event in this pathway that ultimately
leads to loss of chromosome 7 and MDS in children. Through our recent studies on pediatric MDS, we
identified germline heterozygous mutations in two interferon-inducible genes on chromosome 7-SAMD9 and
SAMD9L-that result in growth suppression when exogenously expressed in tissue culture cells and are
associated with monosomy 7 in children with a range of different myeloid abnormalities. Curiously, the copy
of chromosome 7 that is lost in these patients universally is the copy that harbors the mutant allele. Thus, it
appears that in this context, monosomy 7 is an adaptation to the cellular effect of these mutations and while
likely providing a mechanism for hematopoietic cells to grow in these patients, the loss of one copy of
chromosome 7 can lead to MDS or other hematopoietic abnormalities. These genomic and clinical findings
establish a strong scientific premise to investigate the cellular and functional impacts of SAMD9L mutations
in human and mouse hematopoietic cells with a long-term goal to understand how these mutations can
ultimately lead to MDS with monosomy 7. We hypothesize that expression of mutant SAMD9L decreases
hematopoietic cell growth and differentiation, and that different SAMD9L alleles can cooperate with cell
intrinsic or extrinsic factors to influence hematopoietic phenotypes. We will test our hypothesis with the
following specific aims using a combination of genetic tools and functional assays in human and mouse
hematopoietic cells. Specific Aim 1: We will test the in vitro impact of different SAMD9L mutations in primary
hematopoietic cells. Specific Aim 2: We will determine the effect of Samd9l alleles on self-renewal and
transformation. Specific Aim 3: We will test the contribution of environmental stress and SAMD9L expression
on hematopoietic cell growth and differentiation in human cells. The identification of germline mutations in
SAMD9 or SAMD9L in children with MDS is a significant advancement in the field of pediatric myeloid
neoplasms. Our proposed studies will define the role of both mutant and wild-type SAMD9L in hematopoiesis,
the results of which will ultimately impact how patients with these mutations are clinically managed. Not only
will this proposal significantly enhance our knowledge of SAMD9L biology, but we will broadly address how
chromosomal aneuploidy can be an adaptive response to cellular stresses, which is likely a shared
mechanism across different developmental abnormalities or cancers.

## Key facts

- **NIH application ID:** 10072074
- **Project number:** 5R01HL144653-03
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Jeffery M Klco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $448,750
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072074

## Citation

> US National Institutes of Health, RePORTER application 10072074, Cellular and functional impact of SAMD9L mutations on hematopoiesis and myelodysplasia (5R01HL144653-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10072074. Licensed CC0.

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