The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia
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.
Authors
- Olli Lohi (ORCID: https://orcid.org/0000-0001-9195-0797)
- Ronald W. Stam (ORCID: https://orcid.org/0000-0003-4986-1656)
- Pauline Schneider (ORCID: https://orcid.org/0000-0003-0162-9436)
- Pablo Menéndez (ORCID: https://orcid.org/0000-0001-9372-1007)
- Zhongshan Cheng (ORCID: https://orcid.org/0000-0002-6746-5182)
- Louise Ahlgren
- Linda Fogelstrand (ORCID: https://orcid.org/0000-0003-3698-8519)
- Anna Andersson (ORCID: https://orcid.org/0000-0002-2904-1311)
- Tanja A. Grüber (ORCID: https://orcid.org/0000-0003-1072-7257)
- Rob Pieters (ORCID: https://orcid.org/0000-0003-2997-3570)
- Jing Ma (ORCID: https://orcid.org/0000-0003-2910-2628)
- Varsha Singh (ORCID: https://orcid.org/0000-0002-2761-7102)
- Mattias Pilheden (ORCID: https://orcid.org/0000-0002-9235-1953)
- Katja Pokrovskaja Tamm (ORCID: https://orcid.org/0000-0001-6359-1256)
- Minjun Yang (ORCID: https://orcid.org/0000-0002-3324-1498)
- Maud Maillard (ORCID: https://orcid.org/0000-0002-6615-3136)
- Jun J. Yang (ORCID: https://orcid.org/0000-0002-0770-9659)
- Guangchun Song (ORCID: https://orcid.org/0000-0001-9626-2598)
- Birgitte Lausen (ORCID: https://orcid.org/0000-0002-5306-0774)
- Jonas Abrahamsson (ORCID: https://orcid.org/0000-0002-9240-3522)
- Cornelis Jan Pronk (ORCID: https://orcid.org/0000-0002-0073-9660)
- Hanne Vibeke Marquart (ORCID: https://orcid.org/0000-0001-9740-6522)
- Anders Castor
- Gisela Barbany (ORCID: https://orcid.org/0000-0003-3185-2962)
- Karin Lindkvist‐Petersson (ORCID: https://orcid.org/0000-0002-5209-3160)
- Helena Sturesson
- Jinghui Zhang (ORCID: https://orcid.org/0000-0003-3350-9682)
- Huanbin Zhao (ORCID: https://orcid.org/0009-0001-4418-6770)
- Michael P. Walsh (ORCID: https://orcid.org/0009-0000-4293-5291)
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- University of Copenhagen (DK)
- Hospital Sant Joan de Déu Barcelona (ES)
- St. Jude Children's Research Hospital (US)
- Lund University (SE)
- Sahlgrenska University Hospital (SE)
- Rigshospitalet (DK)
- Karolinska Institutet (SE)
- Josep Carreras Leukaemia Research Institute (ES)
- Spanish Clinical Research Network (ES)
- Tampere University Hospital (FI)
- Princess Máxima Center (NL)
- Tampere University (FI)
- Skåne University Hospital (SE)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Medical Research Network (US)
- Universitat de Barcelona (ES)
- University of Gothenburg (SE)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-08
- DOI
- https://doi.org/10.1038/s41467-025-64190-8
- Citations
- 2
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 3.76
Funders
- Cancerfonden
- Crafoordska Stiftelsen
- Lunds Universitet
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Science for Life Laboratory