# Programmed necrosis regulation of leukemic transformation

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2020 · —

## Abstract

Cancer arises from the acquisition of multiple genetic alterations, often preceded by expansion of a clonal cell
population with a growth or survival advantage. Clonally restricted blood cell development (hematopoiesis) is a
common feature in benign and malignant blood disorders. Whole genome genetic studies have identified driver
mutations associated with clonal hematopoietic diseases such as myelodysplastic syndrome (MDS), and acute
myelogenous leukemia (AML) [1-4]. Subsequent studies showed that normal individuals may also harbor clonal
hematopoiesis that is associated with increased risk of hematopoietic as cardiovascular disease (CVD) [5, 6].
Clonal hematopoiesis develops into MDS or AML at a low frequency (~1%), increasing to 80% once low blood
counts develop. AML and MDS prognoses are poor, with limited treatment options. Next generation sequencing
(NGS) of genes mutated in clonal hematopoiesis is clinically available but does not predict who will progress to
from clonal hematopoiesis to MDS or AML. A key question in the field is: What are the factors that predispose
to progression from clonal hematopoiesis to MDS or AML?
The overarching hypothesis is that bone marrow inflammation triggers programmed necrosis in
hematopoietic stem and progenitor cells. This in turn sets up a feed-forward inflammatory
response that can drive clonal expansion and evolution to MDS and AML from clonal
hematopoiesis. Interrupting cell death signaling or altering inflammatory signaling has the
potential to prevent disease evolution for therapeutic benefit.
Aim 1: Compare and contrast the impact of chronic inflammation on inflammatory and cell death signaling in
mouse models of mutations found in clonal hematopoiesis and mouse models of unrestrained necrosis to
determine the molecular decision drivers and how these drivers alter clonal expansion, differentiation, and
clonal evolution (acquisition of additional mutations).
Aim 2. Determine whether pharmacologic inhibition (GSK RIPK1 inhibitor tool compound) or genetic
inactivation of either Rip1 kinase or RipK1 scaffolding function will prevent clonal expansion and clonal
evolution. Determine whether inhibiting cytokines (Enbrel, Humira) will prevent clonal expansion and clonal
evolution.
Aim 3: Determine whether genetically determined changes in expression of genes that drive necroptosis or
innate immune inflammation and their regulatory genetic variants (SNPs), A) associate significantly with risk
of human anemia, MDS, AML B) cooperate with mutations associated with CHIP (TET2, ASXL1) in the risk of
human anemia, MDS and AML.
This proposal will fill an important gap in our knowledge of the biology of clonal hematopoiesis, MDS and AML
in that it will identify gene pathways that underlie a germline genetic predisposition to progression to
symptomatic disease. These studies have the potential to fundamentally change the approach to MDS as well as
clonal hematopoiesis by identifying patients at risk of progression t...

## Key facts

- **NIH application ID:** 10012486
- **Project number:** 1I01BX004365-01A1
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Sandra S Zinkel
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10012486

## Citation

> US National Institutes of Health, RePORTER application 10012486, Programmed necrosis regulation of leukemic transformation (1I01BX004365-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10012486. Licensed CC0.

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