# The Molecular and Biochemical Function of SAMD9 and SAMD9L in Pediatric MDS

> **NIH NIH F32** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2021 · $68,562

## Abstract

Project Summary:
Myelodysplastic syndrome (MDS) is a heterogeneous group of diseases affecting hematopoietic stem cells.
Children with this disorder have impaired hematopoiesis resulting in peripheral blood cytopenias, hypocellular
bone marrows, and are frequently associated with chromosome 7 deletions (monosomy 7). We recently
identified heterozygous germline mutations in sterile alpha motif (SAM) domain-9 (SAMD9) and its paralog,
SAMD9-like (SAMD9L) in children with monosomy 7 mediated MDS. Surprisingly, the monosomy 7 clone that
expands in the bone marrow universally lacks the germline mutation suggesting there is strong selective
pressure against the growth of hematopoietic stem cells expressing the mutant proteins. Expression of SAMD9
and SAMD9L is induced by interferons and other inflammatory stimuli and causes reduced cell division and cell
growth. Most pathogenic mutations found in patients dramatically enhance these effects, exaggerating the anti-
proliferative effects. Our data strongly suggest that SAMD9 and SAMD9L play an important role in pediatric
MDS, but there is an inadequate understanding of the cellular and biochemical function of these proteins. The
rigor of these findings provides a strong scientific premise to investigate the molecular and biochemical
function of these proteins in order to understand their functional role in the development of MDS with
monosomy 7. I hypothesize that the hematopoietic cell growth suppression resulting from the expression of
mutant SAMD9 or SAMD9L is secondary to changes their protein-protein interaction networks and biochemical
function preceding Monosomy 7 development. I will test these hypotheses in the following specific aims using
human hematopoietic cells. In specific aim 1, I will test the hypothesis that protein-protein interactions of
SAMD9 and SAMD9L play a regulatory role in hematopoietic cell growth. In specific aim 2, I will define the
biochemical structure and function of SAMD9 and SAMD9L domain(s) necessary for the inhibition of cellular
growth. We don’t know the mechanism(s) SAMD9 and SAMD9L employ that leads to the selection of
monosomy 7 cells which can progress to MDS. My proposed studies aim to fill these knowledge gaps and will
ultimately help drive the field of pediatric MDS research forward, potentially leading to new approaches for the
treatment of children with germline SAMD9 and SAMD9L mutations.

## Key facts

- **NIH application ID:** 10249947
- **Project number:** 5F32HL152484-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Melvin Edward Thomas
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $68,562
- **Award type:** 5
- **Project period:** 2020-08-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249947

## Citation

> US National Institutes of Health, RePORTER application 10249947, The Molecular and Biochemical Function of SAMD9 and SAMD9L in Pediatric MDS (5F32HL152484-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10249947. Licensed CC0.

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