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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
Nat Commun 16 (1) 8964 [2025-10-08; online 2025-10-08]
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.
Clinical Genomics Lund [Service]
PubMed 41062506
DOI 10.1038/s41467-025-64190-8
Crossref 10.1038/s41467-025-64190-8
pmc: PMC12508131
pii: 10.1038/s41467-025-64190-8