# Project 3: Oncogenic triggers and  their influence on 3D chromosomal  architecture

> **NIH NIH P01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $420,235

## Abstract

SUMMARY – PROJECT 3 (AIFANTIS)
Recent studies have offered the first comprehensive maps of three-dimensional (3D) chromosomal
interactions. The 3D structure of chromatin is defined in part by the organization of chromatin into highly
conserved topologically associating domains (TADs). Studies presented in Project 1 and 2 directly address the
role of key “structural” elements of TAD boundaries (CTCF/Cohesin) in human cancer, including B cell and T
cell malignancy (leukemia and lymphoma). In Project 3, we will test the hypothesis that 3D chromatin structure
is not only affected by CTCF/Cohesin alterations but also by mutations that affect specific epigenetic regulators
and by oncogenic transcription factors. For these studies, we will use T cell leukemia (T-ALL), as a model of
study. We will test whether T-ALL oncogenes (the transcription factor NOTCH1, the main driver in this disease,
mutated or activated in 90% of human T-ALL) use 3D DNA looping events to induce expression of gene-
targets and non-protein coding RNAs that control the function of leukemia cells, including cells that can initiate
the disease (leukemia initiating cells), that are characterized by the overexpression of the NOTCH1
transcriptional target MYC. In addition to oncogenic (NOTCH1, MYC) activation, chromosomal topology can
also be influenced by epigenetic regulators, and it was shown that T-ALL is a disease characterized by
recurrent inactivating mutations in genes that can affect DNA and histone modifications, including genes that
affect DNA methylation (DNMT3A), promoter (EZH2) and enhancer (EP300) activity. We thus hypothesize that
in human leukemia oncogenes (NOTCH1) and tumor suppressors (DNMT3A, EZH2, EP300) cause aberrant
3D chromatin organization changes and that targeted drug treatments are able to correct these defects. We
test this hypothesis in three Aims. Aim 1 assesses the ability of oncogenes like NOTCH1 to directly alter
CTCF/Cohesin distribution leading to aberrant chromosomal architecture. Aim 2 tests the hypothesis that drugs
that target either oncogenic signaling pathways (NOTCH pathway inhibitors) or altered epigenetic states (BET
inhibitors, targeting active H3K27ac-marked areas) can correct 3D chromosomal structure. Finally, Aim 3
focuses on potential effects of selected T-ALL somatic mutations targeting epigenetic regulators and examines
their impact on chromosomal topology. We believe that these studies will complement Projects 1 and 2 that
focus on the impact of CTCF/Cohesin alterations in blood cancer and generate new paradigms of gene
expression regulation in human leukemia.

## Key facts

- **NIH application ID:** 9952336
- **Project number:** 5P01CA229086-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Iannis Aifantis
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $420,235
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952336

## Citation

> US National Institutes of Health, RePORTER application 9952336, Project 3: Oncogenic triggers and  their influence on 3D chromosomal  architecture (5P01CA229086-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9952336. Licensed CC0.

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