# Hematopoietic consequences of gain-of-function SAMD9 and SAMD9L mutations

> **NIH NIH K08** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $108,476

## Abstract

PROJECT SUMMARY
Heterozygous germline mutations in SAMD9 and SAMD9L have recently been described as a new class of MDS
predisposing lesions and are present in approximately 10-20% of pediatric MDS cases. We and others have
shown in published reports that MDS-associated germline mutations in SAMD9/9L increase the antiproliferative
activity of the encoded protein and lead to hypocellular bone marrow with decreased myeloid cell numbers. In
addition, we have shown that the development of a myeloid disease is associated with partial or full loss of
chromosome 7 that results from the non-random loss of the pathologic mutation. Interestingly, somatic revertant
mutations including in cis single nucleotide changes and conversion of the mutant allele to the wild-type through
uniparental disomy occur in some cases which leads to hematopoietic recovery. Remarkably, some patients
with monosomy 7, leading to a presumptive diagnosis of MDS, also achieve hematopoietic recovery through
spontaneous disappearance of the monosomy 7 clone. These data lead to the hypothesis that gain-of-
function (GoF) SAMD9/9L proteins are cytotoxic and cause strong selective pressure for cells lacking
the mutant allele. The molecular mechanisms through which SAMD9/9L GoF mutations inhibit myelopoiesis,
and the spectrum of secondary mutations leading to either MDS, MDS/AML (e.g. SETBP1), or spontaneous
recovery is unknown. The proposed studies will investigate these questions through two specific aims: 1.) to
determine the molecular and functional impact of mutant SAMD9 and SAMD9L expression during myeloid
differentiation using and iPSC model system of pediatric MDS, and 2.) to determine the clonal architecture of
cells expressing mutant SAMD9 and SAMD9L using serial patient samples and single cell genomics.
A Mentored Clinical Scientist Research Career Development Award (K08) will provide the candidate with the
amount of protected time needed to achieve his career goal of independence as a physician scientist and focus
on improving the clinical outcomes of pediatric MDS patients through understanding the mechanisms of their
disease pathogenesis. A strong career development plan including an experienced and successful faculty
advisory committee, clear plans for progress assessments, and attendance at numerous courses, lectures, and
workshops to increase proficiency in technical and management skills will accompany these research goals to
ensure success as an independent physician scientist. This award will be completed at St. Jude Children’s
Research Hospital (St. Jude), one of the world’s leading academic institutions focused on the research and
treatment of pediatric catastrophic diseases, making it an exemplary location for an early career physician
scientist to develop his career. In addition to the strong institutional support, St. Jude offers unmatched research
support with facilities including the Genome Sequencing Facility at the Hartwell Center, a Flow Cytometry and
Cell Sor...

## Key facts

- **NIH application ID:** 9871835
- **Project number:** 1K08HL150282-01
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Jason Ross Schwartz
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $108,476
- **Award type:** 1
- **Project period:** 2020-02-01 → 2020-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9871835

## Citation

> US National Institutes of Health, RePORTER application 9871835, Hematopoietic consequences of gain-of-function SAMD9 and SAMD9L mutations (1K08HL150282-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9871835. Licensed CC0.

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