The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia
Abstract
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.
Article Details
Authors (29)
Louise Ahlgren
Mattias Pilheden
Helena Sturesson
Guangchun Song
Key Laboratory of Agro-products Quality and Safety Control in Storage and Transport Process, Ministry of Agriculture and Rural Affairs
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
Department of Pharmacy and Pharmaceutical Sciences
Tanja A. Gruber
Ronald W. Stam
Jing Ma
State Key Laboratory of Coordination Chemistry, School of Chemistry
Anna K. Hagström-Andersson