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Discovery of Cis-Regulatory Mechanisms via Non-Coding Mutations in Acute Lymphoblastic Leukemia

Aydın, Efe LU ; Woodward, Eleanor L. LU ; Dushime, Gladys Telliam LU ; Gunnarsson, Rebeqa LU ; Lilljebjörn, Henrik LU orcid ; Moura-Castro, Larissa H. LU orcid ; Fioretos, Thoas LU ; Johansson, Bertil LU ; Paulsson, Kajsa LU and Yang, Minjun LU (2025) In Genes Chromosomes and Cancer 64(3).
Abstract

The non-coding genome, constituting 98% of human DNA, remains largely unexplored, yet holds potential for identifying new biomarkers and therapeutic targets in acute lymphoblastic leukemia (ALL). In this study, we conducted a systematic analysis of recurrent somatic non-coding single nucleotide variants (SNVs) in pediatric B-cell precursor (BCP) ALL. We leveraged whole genome sequencing (WGS) data from 345 pediatric BCP ALL cases, representing all major genetic subtypes and identified 346 mutational hotspots that harbored somatic SNVs in at least three cases. Through the integration of paired RNA sequencing along with published ChIP-seq and ATAC-seq data, we found 128 non-coding hotspots associated with differentially expressed genes... (More)

The non-coding genome, constituting 98% of human DNA, remains largely unexplored, yet holds potential for identifying new biomarkers and therapeutic targets in acute lymphoblastic leukemia (ALL). In this study, we conducted a systematic analysis of recurrent somatic non-coding single nucleotide variants (SNVs) in pediatric B-cell precursor (BCP) ALL. We leveraged whole genome sequencing (WGS) data from 345 pediatric BCP ALL cases, representing all major genetic subtypes and identified 346 mutational hotspots that harbored somatic SNVs in at least three cases. Through the integration of paired RNA sequencing along with published ChIP-seq and ATAC-seq data, we found 128 non-coding hotspots associated with differentially expressed genes nearby, which were enriched for cis-regulatory elements, demonstrating the effectiveness of multi-omics integration in distinguishing pathogenic mutations from passengers. We identified one mutational hotspot that was associated with increased expression of the leukemia-associated gene NRAS in three primary ALLs. Micro-C analysis in the leukemia cell line demonstrated interactions between the hotspot region and NRAS regulatory elements. Dual luciferase assays indicated that the mutations disrupted regulatory interactions and CRISPR-mediated deletion of the region significantly upregulated NRAS, confirming the hypothesized regulatory link. Altogether, we provide new insights into the functional roles of non-coding mutations in leukemia.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
B-cell precursor acute lymphoblastic leukemia, cis-regulatory elements, leukemogenesis, multi-omics, non-coding mutations
in
Genes Chromosomes and Cancer
volume
64
issue
3
article number
e70045
publisher
Wiley-Liss Inc.
external identifiers
  • scopus:105001986866
  • pmid:40145864
ISSN
1045-2257
DOI
10.1002/gcc.70045
language
English
LU publication?
yes
id
91d2f9dd-0854-489d-8288-15975c723981
date added to LUP
2025-08-26 11:54:40
date last changed
2025-10-21 17:30:59
@article{91d2f9dd-0854-489d-8288-15975c723981,
  abstract     = {{<p>The non-coding genome, constituting 98% of human DNA, remains largely unexplored, yet holds potential for identifying new biomarkers and therapeutic targets in acute lymphoblastic leukemia (ALL). In this study, we conducted a systematic analysis of recurrent somatic non-coding single nucleotide variants (SNVs) in pediatric B-cell precursor (BCP) ALL. We leveraged whole genome sequencing (WGS) data from 345 pediatric BCP ALL cases, representing all major genetic subtypes and identified 346 mutational hotspots that harbored somatic SNVs in at least three cases. Through the integration of paired RNA sequencing along with published ChIP-seq and ATAC-seq data, we found 128 non-coding hotspots associated with differentially expressed genes nearby, which were enriched for cis-regulatory elements, demonstrating the effectiveness of multi-omics integration in distinguishing pathogenic mutations from passengers. We identified one mutational hotspot that was associated with increased expression of the leukemia-associated gene NRAS in three primary ALLs. Micro-C analysis in the leukemia cell line demonstrated interactions between the hotspot region and NRAS regulatory elements. Dual luciferase assays indicated that the mutations disrupted regulatory interactions and CRISPR-mediated deletion of the region significantly upregulated NRAS, confirming the hypothesized regulatory link. Altogether, we provide new insights into the functional roles of non-coding mutations in leukemia.</p>}},
  author       = {{Aydın, Efe and Woodward, Eleanor L. and Dushime, Gladys Telliam and Gunnarsson, Rebeqa and Lilljebjörn, Henrik and Moura-Castro, Larissa H. and Fioretos, Thoas and Johansson, Bertil and Paulsson, Kajsa and Yang, Minjun}},
  issn         = {{1045-2257}},
  keywords     = {{B-cell precursor acute lymphoblastic leukemia; cis-regulatory elements; leukemogenesis; multi-omics; non-coding mutations}},
  language     = {{eng}},
  number       = {{3}},
  publisher    = {{Wiley-Liss Inc.}},
  series       = {{Genes Chromosomes and Cancer}},
  title        = {{Discovery of Cis-Regulatory Mechanisms via Non-Coding Mutations in Acute Lymphoblastic Leukemia}},
  url          = {{http://dx.doi.org/10.1002/gcc.70045}},
  doi          = {{10.1002/gcc.70045}},
  volume       = {{64}},
  year         = {{2025}},
}