# Epigenetic drivers of cancer progression

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $423,649

## Abstract

This renewal application continues to develop experimental, conceptual and computational approaches to
understanding epigenetic drivers of cancer progression. A major discovery in the current period was that
pancreatic cancer metastasis is driven by large-scale changes in the epigenomic landscape in the absence of
metastasis driver mutations. We also developed a powerful computational approach to measuring the
epigenomic landscape including deep properties such as entropy that drive pluripotency and the variable gene
expression underlying tumor cell heterogeneity. The central question in the current application is the relationship
between epigenetic modifiers (typically mutated in cancer) driving malignant changes in the epigenetic
landscape, and their target mediator genes on the altered landscape (often unknown) and their relationship to
gene expression and phenotypic heterogeneity. We will focus on acute myeloid leukemia (AML) because of the
direct involvement of epigenetic modifier mutations in disease pathogenesis, the pressing need to identify their
mediators, strong evidence of the clinical and prognostic impact of epigenetic heterogeneity in AML, the
availability of a richly annotated set of primary patient samples via collaboration with Ravi Majeti (Stanford
University), and the ease of experimental manipulation of AML cell lines and primary hematopoietic
stem/progenitor cells (HSPC) for validation. Our first Aim is to generate comprehensive genome-wide maps of
the epigenetic landscape in AML, encompassing high-dimensional properties such as DNA methylation entropy.
We will: perform DNA methylation potential energy landscape analysis of primary AML samples with genetic
mutations of epigenetic modifiers that affect DNA methylation or chromatin directly; perform similar landscape
analysis of normal early hematopoietic progenitors; measure higher order chromatin structure to integrate DNA
methylation, modifiers and mediators; and identify gene networks regulating gene expression and gene
expression variability. Our second Aim is to perturb the epigenetic landscape to modify gene expression,
expression variability and phenotype. We will: genetically engineer HSPCs to perturb epigenetic modifiers; target
sites of differential entropic sensitivity on the epigenetic landscape affecting gene expression heterogeneity;
validate functional roles for epigenetic mediators of the destabilized epigenetic landscape in AML; and determine
the impact of epigenetic therapeutics on DNA methylation entropy in AML and HSPCs. This work will bring to
bear powerful new mathematical and laboratory methods to integrate the epigenetic landscape with gene
expression mean and variability, in normal and malignant hematopoietic cells, and enable us to understand gene
networks, epigenetic instability and phenotypic plasticity in the context of experimental hematology and cancer
progression.

## Key facts

- **NIH application ID:** 10450871
- **Project number:** 5R01CA054358-29
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** ANDREW P. FEINBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,649
- **Award type:** 5
- **Project period:** 1991-05-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450871

## Citation

> US National Institutes of Health, RePORTER application 10450871, Epigenetic drivers of cancer progression (5R01CA054358-29). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10450871. Licensed CC0.

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