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The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia

Ahlgren, Louise LU ; Pilheden, Mattias LU ; Sturesson, Helena LU ; Song, Guangchun ; Walsh, Michael P ; Yang, Minjun LU ; Maillard, Maud ; Zhao, Huanbin ; Cheng, Zhongshan and Singh, Varsha LU , et al. (2025) In Nature Communications 16(1).
Abstract

To study the mechanisms of relapse in KMT2A-rearranged (KMT2A-r) acute lymphoblastic (ALL) and acute myeloid leukemia (AML), we performed whole-genome and exome sequencing of infants and children with relapsed ALL/AML (n = 36), and longitudinal deep-sequencing of 257 samples in 30 patients. Somatic alterations in drug-response genes, most commonly in TP53 and IKZF1 (64%), were highly enriched in early relapse ALL (79%, 9-36 months after diagnosis), but rare in very early relapse ALL (<9 months, 9%). A marked chemotherapy-exposure signature was detected for mutations in early relapse ALL but not in very early ALL or AML relapse, in line with different mechanisms of relapse. Longitudinal analyses could track residual leukemia cells,... (More)

To study the mechanisms of relapse in KMT2A-rearranged (KMT2A-r) acute lymphoblastic (ALL) and acute myeloid leukemia (AML), we performed whole-genome and exome sequencing of infants and children with relapsed ALL/AML (n = 36), and longitudinal deep-sequencing of 257 samples in 30 patients. Somatic alterations in drug-response genes, most commonly in TP53 and IKZF1 (64%), were highly enriched in early relapse ALL (79%, 9-36 months after diagnosis), but rare in very early relapse ALL (<9 months, 9%). A marked chemotherapy-exposure signature was detected for mutations in early relapse ALL but not in very early ALL or AML relapse, in line with different mechanisms of relapse. Longitudinal analyses could track residual leukemia cells, clonal drug responses, and the upcoming relapse. These results highlight that KMT2A-r ALL and AML evade therapy differently and provide insights into the mechanisms of relapse in this highly lethal form of pediatric acute leukemia.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
Humans, Myeloid-Lymphoid Leukemia Protein/genetics, Histone-Lysine N-Methyltransferase/genetics, Leukemia, Myeloid, Acute/genetics, Infant, Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics, Child, Preschool, Child, Female, Male, Gene Rearrangement, Recurrence, Mutation, Exome Sequencing, Ikaros Transcription Factor/genetics, Tumor Suppressor Protein p53/genetics, Genomics, Adolescent
in
Nature Communications
volume
16
issue
1
article number
8964
pages
14 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:41062506
  • scopus:105018250401
ISSN
2041-1723
DOI
10.1038/s41467-025-64190-8
language
English
LU publication?
yes
additional info
© 2025. The Author(s).
id
5b19b447-6d2f-4a92-8e2f-921adf3b71da
date added to LUP
2025-10-20 11:32:09
date last changed
2025-12-02 07:11:32
@article{5b19b447-6d2f-4a92-8e2f-921adf3b71da,
  abstract     = {{<p>To study the mechanisms of relapse in KMT2A-rearranged (KMT2A-r) acute lymphoblastic (ALL) and acute myeloid leukemia (AML), we performed whole-genome and exome sequencing of infants and children with relapsed ALL/AML (n = 36), and longitudinal deep-sequencing of 257 samples in 30 patients. Somatic alterations in drug-response genes, most commonly in TP53 and IKZF1 (64%), were highly enriched in early relapse ALL (79%, 9-36 months after diagnosis), but rare in very early relapse ALL (&lt;9 months, 9%). A marked chemotherapy-exposure signature was detected for mutations in early relapse ALL but not in very early ALL or AML relapse, in line with different mechanisms of relapse. Longitudinal analyses could track residual leukemia cells, clonal drug responses, and the upcoming relapse. These results highlight that KMT2A-r ALL and AML evade therapy differently and provide insights into the mechanisms of relapse in this highly lethal form of pediatric acute leukemia.</p>}},
  author       = {{Ahlgren, Louise and Pilheden, Mattias and Sturesson, Helena and Song, Guangchun and Walsh, Michael P and Yang, Minjun and Maillard, Maud and Zhao, Huanbin and Cheng, Zhongshan and Singh, Varsha and Castor, Anders and Pronk, Cornelis Jan and Marquart, Hanne Vibeke and Lausen, Birgitte and Schneider, Pauline and Barbany, Gisela and Pokrovskaja Tamm, Katja and Abrahamsson, Jonas and Lohi, Olli and Fogelstrand, Linda and Menendez, Pablo and Pieters, Rob and Zhang, Jinghui and Lindkvist-Petersson, Karin and Yang, Jun J and Gruber, Tanja A and Stam, Ronald W and Ma, Jing and Hagström-Andersson, Anna K}},
  issn         = {{2041-1723}},
  keywords     = {{Humans; Myeloid-Lymphoid Leukemia Protein/genetics; Histone-Lysine N-Methyltransferase/genetics; Leukemia, Myeloid, Acute/genetics; Infant; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics; Child, Preschool; Child; Female; Male; Gene Rearrangement; Recurrence; Mutation; Exome Sequencing; Ikaros Transcription Factor/genetics; Tumor Suppressor Protein p53/genetics; Genomics; Adolescent}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia}},
  url          = {{http://dx.doi.org/10.1038/s41467-025-64190-8}},
  doi          = {{10.1038/s41467-025-64190-8}},
  volume       = {{16}},
  year         = {{2025}},
}