Remodeling of 3D chromatin in B cell acute leukemia and its impact on clinical outcome

ABSTRACT
While the outcomes for children with acute lymphoblastic leukemia (ALL) have improved dramatically over the
past four decades, major challenges remain including the burden of conventional therapy and less progress in
major subgroups making ALL one of the leading causes of cancer death in children. Thus, targeted, more effec-
tive therapies are urgently needed. The current project builds on our recent studies implicating the epigenome
in transformation and response to therapy. Recent advances in chromatin conformation capture techniques have
revolutionized our understanding of chromatin organization and have provided novel insights at an unprece-
dented level of detail. Several studies have identified biologically-relevant structures in DNA-DNA contact maps,
such as A/B compartments, topologically-associating domains (TADs), and 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 chro-
matin organization on a genome-wide scale in cancer patients or how such disruptions modify the promoter-
enhancer landscape leading to leukemia initiation and therapy resistance and relapse. This study aims to ad-
dress these gaps by comparing the chromatin landscape in B ALL samples and normal B precursor cells to
identify chromatin architecture associated with transformation and to chart the evolution of topographic changes
from diagnosis to relapse using paired samples to discover 3D alterations associated with tumor progression. In
preliminary data, we have analyzed a small pilot cohort of 12 patients with matched diagnosis/relapse samples.
In this small cohort, we have already identified chromatin reorganization events at multiple levels: compartment
switches, changes in intra-TAD chromatin interactions, establishment of enhancer-promoter loops and structural
alterations that directly affect 3D topology. Such changes will be validated in preclinical models using genetically
engineered cell lines in vitro and in vivo as well as patient derived xenografts (PDX). Finally, to examine the
subclonal composition of promoter-enhancer loops we will use single cell DNA/RNA FISH and will use the same
methodology to track evolution in PDX models.

Grant Number: 5R01CA260028-05
NIH Institute/Center: NIH
Principal Investigator: William Carroll