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

Louise Ahlgren; Mattias Pilheden; Helena Sturesson; Guangchun Song; Michael P. Walsh; Minjun Yang; Maud Maillard; Huanbin Zhao; Zhongshan Cheng; Varsha Singh; Anders Castor; Cornelis Jan Pronk; Hanne Vibeke Marquart; Birgitte Lausen; Pauline Schneider; Gisela Barbany; Katja Pokrovskaja Tamm; Jonas Abrahamsson; Olli Lohi; Linda Fogelstrand; Pablo Menendez; Rob Pieters; Jinghui Zhang; Karin Lindkvist-Petersson; Jun J. Yang; Tanja A. Gruber; Ronald W. Stam; Jing Ma; Anna K. Hagström-Andersson

doi:10.1038/s41467-025-64190-8

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

Louise Ahlgren, Mattias Pilheden, Helena Sturesson, Guangchun Song, Michael P. Walsh, Minjun Yang, Maud Maillard, Huanbin Zhao, Zhongshan Cheng, Varsha Singh, Anders Castor, Cornelis Jan Pronk, Hanne Vibeke Marquart, Birgitte Lausen, Pauline Schneider, Gisela Barbany, Katja Pokrovskaja Tamm, Jonas Abrahamsson, Olli Lohi, Linda FogelstrandPablo Menendez, Rob Pieters, Jinghui Zhang, Karin Lindkvist-Petersson, Jun J. Yang, Tanja A. Gruber, Ronald W. Stam, Jing Ma, Anna K. Hagström-Andersson

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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, 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.

Original language	English
Article number	8964
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-64190-8
Publication status	Published - 2025
Publication type	A1 Journal article-refereed

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Publication forum level 3

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General Chemistry
General Biochemistry,Genetics and Molecular Biology
General
General Physics and Astronomy

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The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemiaFinal published version, 1.7 MBLicence: CC BY

https://urn.fi/URN:NBN:fi:tuni-2025103010265Licence: CC BY

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Ahlgren, L., Pilheden, M., Sturesson, H., Song, G., Walsh, M. P., Yang, M., Maillard, M., Zhao, H., Cheng, Z., Singh, V., Castor, A., Pronk, C. J., Marquart, H. V., Lausen, B., Schneider, P., Barbany, G., Pokrovskaja Tamm, K., Abrahamsson, J., Lohi, O., ... Hagström-Andersson, A. K. (2025). The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia. Nature Communications, 16(1), Article 8964. https://doi.org/10.1038/s41467-025-64190-8

@article{f57313924066473d8f48ba3b2beddcde,

title = "The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia",

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, 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.",

author = "Louise Ahlgren and Mattias Pilheden and Helena Sturesson and Guangchun Song and Walsh, \{Michael P.\} and Minjun Yang and Maud Maillard and Huanbin Zhao and Zhongshan Cheng and Varsha Singh and Anders Castor and Pronk, \{Cornelis Jan\} and Marquart, \{Hanne Vibeke\} and Birgitte Lausen and Pauline Schneider and Gisela Barbany and \{Pokrovskaja Tamm\}, Katja and Jonas Abrahamsson and Olli Lohi and Linda Fogelstrand and Pablo Menendez and Rob Pieters and Jinghui Zhang and Karin Lindkvist-Petersson and Yang, \{Jun J.\} and Gruber, \{Tanja A.\} and Stam, \{Ronald W.\} and Jing Ma and Hagstr{\"o}m-Andersson, \{Anna K.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

doi = "10.1038/s41467-025-64190-8",

language = "English",

volume = "16",

journal = "Nature Communications",

issn = "2041-1723",

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Ahlgren, L, Pilheden, M, Sturesson, H, Song, G, Walsh, MP, Yang, M, Maillard, M, Zhao, H, Cheng, Z, Singh, V, Castor, A, Pronk, CJ, Marquart, HV, Lausen, B, Schneider, P, Barbany, G, Pokrovskaja Tamm, K, Abrahamsson, J, Lohi, O, Fogelstrand, L, Menendez, P, Pieters, R, Zhang, J, Lindkvist-Petersson, K, Yang, JJ, Gruber, TA, Stam, RW, Ma, J & Hagström-Andersson, AK 2025, 'The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia', Nature Communications, vol. 16, no. 1, 8964. https://doi.org/10.1038/s41467-025-64190-8

TY - JOUR

T1 - The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia

AU - Ahlgren, Louise

AU - Pilheden, Mattias

AU - Sturesson, Helena

AU - Song, Guangchun

AU - Walsh, Michael P.

AU - Yang, Minjun

AU - Maillard, Maud

AU - Zhao, Huanbin

AU - Cheng, Zhongshan

AU - Singh, Varsha

AU - Castor, Anders

AU - Pronk, Cornelis Jan

AU - Marquart, Hanne Vibeke

AU - Lausen, Birgitte

AU - Schneider, Pauline

AU - Barbany, Gisela

AU - Pokrovskaja Tamm, Katja

AU - Abrahamsson, Jonas

AU - Lohi, Olli

AU - Fogelstrand, Linda

AU - Menendez, Pablo

AU - Pieters, Rob

AU - Zhang, Jinghui

AU - Lindkvist-Petersson, Karin

AU - Yang, Jun J.

AU - Gruber, Tanja A.

AU - Stam, Ronald W.

AU - Ma, Jing

AU - Hagström-Andersson, Anna K.

PY - 2025

Y1 - 2025

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-025-64190-8

DO - 10.1038/s41467-025-64190-8

M3 - Article

C2 - 41062506

AN - SCOPUS:105018250401

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 8964

ER -

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

Abstract

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