R01CA252239
Project Grant
Overview
Grant Description
Dynamic 3D Chromatin Remodeling in Acute Leukemia - Resubmission - 1 - Abstract
Recent advances in chromatin conformation capture techniques have revolutionized our understanding of chromatin organization and have provided novel insights at an unprecedented level of detail. Several studies have identified biologically-relevant structures in DNA-DNA contact maps, such as A/B compartments, topologically-associating domains (TADs), insulated neighborhoods, and have elucidated the role of chromatin architecture in gene regulation and maintenance of cell identity.
A handful of very recent studies from our lab and others have shown that aberrant TAD activation or "rewiring" promoter-enhancer interactions can promote cancer growth. However, no study has yet addressed the disruptions of chromatin organization on a genome-wide scale in cancer patients or how such disruptions modify the promoter-enhancer landscape leading to drug resistance and relapse.
Using primary acute leukemia patient samples, we have, for the first time, identified recurrent TAD disruptions in leukemia involving key oncogenes (e.g. NOTCH1, MYC) and their targets. For example, we identified a recurrent disruption of 3D chromatin topology in the MYC locus at a previously uncharacterized non-coding CTCF-bound region that insulates MYC from downstream enhancers. This disruption enables chromatin interactions between the MYC oncogene and the downstream enhancers leading to an increase in MYC expression.
Based on our preliminary results, we propose to investigate 3D chromosomal landscape reorganization as a new mechanism of cancer initiation, progression, and relapse, and to discover novel non-coding regulatory elements (enhancer 3D hubs and their TAD boundaries) that drive leukemia. To this end, we will first profile and analyze a large cohort of leukemia patients using Hi-C and H3K27ac HiChIP both at diagnosis and at relapse to identify recurrent relapse-specific 3D reorganization events. We will combine computational methods with orthogonal CRISPR strategies to discover transcription factors and epigenetic modifiers that enable the emergence of drug resistance via the rewiring of enhancer-promoter chromatin looping.
We will then focus on enhancer hubs: we and others have shown that enhancers that are densely connected with target promoters and other enhancers (i.e. enhancer hubs) are robust regulators of gene expression and their disruption can impact the regulation of multiple genes. Based on these findings, we will test whether such enhancer hubs and their 3D topology can be drivers of drug resistance by activating oncogenic loci in vitro and in vivo.
Our proposed study will not only elucidate the role of 3D architecture in leukemia at diagnosis and relapse, but it will also advance our understanding of resistance to therapy and develop new approaches to overcome it.
Recent advances in chromatin conformation capture techniques have revolutionized our understanding of chromatin organization and have provided novel insights at an unprecedented level of detail. Several studies have identified biologically-relevant structures in DNA-DNA contact maps, such as A/B compartments, topologically-associating domains (TADs), insulated neighborhoods, and have elucidated the role of chromatin architecture in gene regulation and maintenance of cell identity.
A handful of very recent studies from our lab and others have shown that aberrant TAD activation or "rewiring" promoter-enhancer interactions can promote cancer growth. However, no study has yet addressed the disruptions of chromatin organization on a genome-wide scale in cancer patients or how such disruptions modify the promoter-enhancer landscape leading to drug resistance and relapse.
Using primary acute leukemia patient samples, we have, for the first time, identified recurrent TAD disruptions in leukemia involving key oncogenes (e.g. NOTCH1, MYC) and their targets. For example, we identified a recurrent disruption of 3D chromatin topology in the MYC locus at a previously uncharacterized non-coding CTCF-bound region that insulates MYC from downstream enhancers. This disruption enables chromatin interactions between the MYC oncogene and the downstream enhancers leading to an increase in MYC expression.
Based on our preliminary results, we propose to investigate 3D chromosomal landscape reorganization as a new mechanism of cancer initiation, progression, and relapse, and to discover novel non-coding regulatory elements (enhancer 3D hubs and their TAD boundaries) that drive leukemia. To this end, we will first profile and analyze a large cohort of leukemia patients using Hi-C and H3K27ac HiChIP both at diagnosis and at relapse to identify recurrent relapse-specific 3D reorganization events. We will combine computational methods with orthogonal CRISPR strategies to discover transcription factors and epigenetic modifiers that enable the emergence of drug resistance via the rewiring of enhancer-promoter chromatin looping.
We will then focus on enhancer hubs: we and others have shown that enhancers that are densely connected with target promoters and other enhancers (i.e. enhancer hubs) are robust regulators of gene expression and their disruption can impact the regulation of multiple genes. Based on these findings, we will test whether such enhancer hubs and their 3D topology can be drivers of drug resistance by activating oncogenic loci in vitro and in vivo.
Our proposed study will not only elucidate the role of 3D architecture in leukemia at diagnosis and relapse, but it will also advance our understanding of resistance to therapy and develop new approaches to overcome it.
Awardee
Funding Goals
TO PROVIDE FUNDAMENTAL INFORMATION ON THE CAUSE AND NATURE OF CANCER IN PEOPLE, WITH THE EXPECTATION THAT THIS WILL RESULT IN BETTER METHODS OF PREVENTION, DETECTION AND DIAGNOSIS, AND TREATMENT OF NEOPLASTIC DISEASES. CANCER BIOLOGY RESEARCH INCLUDES THE FOLLOWING RESEARCH PROGRAMS: CANCER CELL BIOLOGY, CANCER IMMUNOLOGY, HEMATOLOGY AND ETIOLOGY, DNA AND CHROMOSOMAL ABERRATIONS, TUMOR BIOLOGY AND METASTASIS, AND STRUCTURAL BIOLOGY AND MOLECULAR APPLICATIONS.
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
New York,
New York
10016
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 394% from $612,931 to $3,027,488.
New York University was awarded
3D Chromatin Remodeling in Leukemia: Novel Insights
Project Grant R01CA252239
worth $3,027,488
from National Cancer Institute in April 2021 with work to be completed primarily in New York New York United States.
The grant
has a duration of 5 years and
was awarded through assistance program 93.396 Cancer Biology Research.
The Project Grant was awarded through grant opportunity NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed).
Status
(Ongoing)
Last Modified 6/20/25
Period of Performance
4/1/21
Start Date
3/31/26
End Date
Funding Split
$3.0M
Federal Obligation
$0.0
Non-Federal Obligation
$3.0M
Total Obligated
Activity Timeline
Transaction History
Modifications to R01CA252239
Additional Detail
Award ID FAIN
R01CA252239
SAI Number
R01CA252239-3008724921
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Private Institution Of Higher Education
Awarding Office
75NC00 NIH National Cancer Institute
Funding Office
75NC00 NIH National Cancer Institute
Awardee UEI
M5SZJ6VHUHN8
Awardee CAGE
3D476
Performance District
NY-12
Senators
Kirsten Gillibrand
Charles Schumer
Charles Schumer
Budget Funding
Federal Account | Budget Subfunction | Object Class | Total | Percentage |
---|---|---|---|---|
National Cancer Institute, National Institutes of Health, Health and Human Services (075-0849) | Health research and training | Grants, subsidies, and contributions (41.0) | $1,210,365 | 100% |
Modified: 6/20/25