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

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Titel: The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia
Autoren: Ahlgren, Louise, Pilheden, Mattias, Sturesson, Helena, Song, Guangchun, Walsh, Michael P, Yang, Minjun, Maillard, Maud, Zhao, Huanbin, Cheng, Zhongshan, Singh, Varsha, Castor, Anders, Pronk, Cornelis Jan, Marquart, Hanne Vibeke, Lausen, Birgitte, Schneider, Pauline, Barbany, Gisela, Pokrovskaja Tamm, Katja, Abrahamsson, Jonas, Lohi, Olli, Fogelstrand, Linda, Menendez, Pablo, Pieters, Rob, Zhang, Jinghui, Lindkvist-Petersson, Karin, Yang, Jun J, Gruber, Tanja A, Stam, Ronald W, Ma, Jing, Hagström-Andersson, Anna K
Weitere Verfasser: Lund University, Faculty of Medicine, Department of Laboratory Medicine, Division of Clinical Genetics, Lunds universitet, Medicinska fakulteten, Institutionen för laboratoriemedicin, Avdelningen för klinisk genetik, Originator, Lund University, Faculty of Medicine, Department of Laboratory Medicine, Lunds universitet, Medicinska fakulteten, Institutionen för laboratoriemedicin, Originator, Lund University, Faculty of Medicine, Department of Experimental Medical Science, Lunds universitet, Medicinska fakulteten, Institutionen för experimentell medicinsk vetenskap, Originator, Lund University, Faculty of Medicine, Department of Experimental Medical Science, Medical Structural Biology, Lunds universitet, Medicinska fakulteten, Institutionen för experimentell medicinsk vetenskap, Medicinsk strukturbiologi, Originator, Lund University, Faculty of Medicine, Department of Laboratory Medicine, Division of Clinical Genetics, Center for Translational Genomics (CTG), Lunds universitet, Medicinska fakulteten, Institutionen för laboratoriemedicin, Avdelningen för klinisk genetik, Centrum för Translationell Genomik (CTG), Originator
Quelle: Nature Communications. 16(1)
Schlagwörter: Medical and Health Sciences, Basic Medicine, Medical Genetics and Genomics (including Gene Therapy), Medicin och hälsovetenskap, Medicinska och farmaceutiska grundvetenskaper, Medicinsk genetik och genomik (Här ingår: Genterapi), Clinical Medicine, Cancer and Oncology, Klinisk medicin, Cancer och onkologi, Pediatrics, Pediatrik
Beschreibung: 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.
Zugangs-URL: https://doi.org/10.1038/s41467-025-64190-8
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  Data: 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.
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      – TitleFull: The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia
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