Nature: 3D genomic analysis reveals changes in different subtypes of leukemia

Acute myeloid leukemia (AML) is the most common leukemia in adults, but it can occur
in people of any age.
AML is characterized by blocked primordial granulocyte differentiation, clonal expansion into the bloodstream and other sites
.
The clinical course of AML is highly heterogeneous, with variable molecular features that are critical
to risk stratification, prognosis, and therapy selection.

A recent study published in the journal Nature suggests that changes in three-dimensional (3D) chromatin structure and associated methylation changes are expected to inform AML subtypes, providing clues
for understanding and treating the disease.

"In this study, we sought to characterize the relationship between DNA methylation and 3D genomic structure in AML cells, and whether demethylating drugs (HMAs) are able to restore normal chromatin structure and gene regulation," the authors write
in the paper.
The study was led
by Feng Yue of Northwestern University and Hong Zheng of the University of Pennsylvania.

The researchers collected 25 samples from AML patients and 7 samples from healthy donors, and performed whole genome sequencing, in situ Hi-C-based chromatin interaction analysis, ATAC-seq, RNA-seq, and CUT&Tag analysis
.
They delineated features
such as chromatin structural compartments, topologically associated domains (TADs), and chromatin rings.

The results highlighted different chromatin structural features between different AML genotypes, and recurrent chromatin rings exhibiting specific enhancer or silencing activity
in different myeloid tissue malignancies.
Subsequent CRISPR gene editing or CRISPR interference experiments and other analyses supported these results
.

"Hijacked enhancers play a role in AML cell growth, as evidenced by CRISPR screening experiments," the authors report
.
"Hijacked silencers have a down-regulating effect, as demonstrated by CRISPR
interference-mediated deinhibition.
"

To better understand the relationship between the 3D genome and chromatin structure, CTCF transcription factor binding, and DNA methylation patterns, the researchers later turned to genome-wide bisulfite sequencing to analyze 18 AML samples and 2 normal PBMC samples, and performed CUT&Tag analysis
on 10 AML samples.
They found that the enhancement of methylation appeared to correspond
to a decrease in CTCF binding, TAD boundary shift, and other chromatin changes.

In addition, they found that when demethylating drugs such as 5-azacytidine or decitabine are present, or when genes encoding DNA methyltransferases in cells are below normal levels, the genomic structure and expression effects associated with AML appear to be reversed
.

"These results suggest that treatment with demethylating drugs may be partially effective by restoring normal chromatin structure
," the authors note.
Combining demethylation drugs with other drugs that restore normal genomic structure may enhance treatment response, thereby improving outcomes
for AML and other cancers.
”

Original text search

Xu, J.
, Song, F.
, Lyu, H.
et al.
Subtype-specific 3D genome alteration in acute myeloid leukaemia.
Nature (2022).
https://doi.
org/10.
1038/s41586-022-05365-x