# Mechanisms of necrosis regulation of hematopoietic stem cell function

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $395,000

## Abstract

Normal hematopoiesis requires stringent control of production of new cells (proliferation) and removal of aging
or damaged cells (programmed cell death). Patients with bone marrow failure disorders such as
Myelodysplastic syndrome (MDS) have increased bone marrow programmed cell death, and increased levels
of death-inducing cytokines such as TNFa. Discoveries in the last several years have demonstrated that in
addition to apoptosis, TNFa also activates a novel form of cell death, programmed necrosis. Apoptotic cells
implode in caspase-driven and immune silent process, whereas necrotic cells explode in a Rip kinase-driven
process, releasing cellular contents (DAMPS) and eliciting an immune response. We find increased Rip1
kinase expression in 70% of MDS patient samples tested suggesting that necroptosis is activated in MDS. We
also find that bone marrow from mouse models harboring known genetic mutations found in MDS (Asxl1-/-,
Asxl1-/-Tet2-/-) display increased Rip1 kinase, suggesting that MDS genetic/epigenetic alterations result in
increased necroptosis signaling that contributes to bone marrow cell death. Substantial data demonstrate that
MDS is a clonal stem cell disorder(Graubert et al., 2012; Walter et al., 2011; Walter et al., 2012; Walter et al.,
2013). A paradox inherent in MDS is that although the MDS-propagating clone has increased competitive
ability, its expansion ultimately results in bone marrow failure. The presence of MDS stem cells and dying
progenitor cells confers decreased function to the coexisting normal stem cells, suggesting that MDS stem and
progenitor cells create a bone marrow environment that is killing normal hematopoietic stem cells. In our
mouse model with unrestrained hematopoietic necrosis, mice die of bone marrow failure with the majority of
the features of human MDS. Furthermore, bone marrow from these mice displayed increased competitive
repopulating ability against wild type bone marrow, but transplanted mice die of bone marrow failure at four
months despite the persistence of wild type bone marrow, suggesting that these necrotic HSC and progenitor
cells can kill wild type HSCs to cause bone marrow failure. Our mice thus shed light on how an MDS clone can
cause bone marrow failure: Our overarching hypothesis is that programmed necrosis in MDS cells triggers an
inflammatory response that kills normal hematopoietic stem cells. This in term enables mutant stem and
progenitor cells to expand and take over the bone marrow, thus driving bone marrow failure. Interrupting the
cell death signaling pathway or altering the inflammatory signaling pathway has the potential to prevent cell
death and re establish bone marrow homeostasis for therapeutic benefit. Aim 1: Will evaluate cell death and
cytokine signaling in genetic mouse models of unrestrained necroptosis, as well as MDS mutations, to identify
the molecular decision drivers, and how these drivers alter bone marrow cell death Aim 2: Will determine
whether inhibiti...

## Key facts

- **NIH application ID:** 10145059
- **Project number:** 5R01HL133559-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Sandra S Zinkel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $395,000
- **Award type:** 5
- **Project period:** 2018-05-03 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145059

## Citation

> US National Institutes of Health, RePORTER application 10145059, Mechanisms of necrosis regulation of hematopoietic stem cell function (5R01HL133559-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10145059. Licensed CC0.

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