Mutational mechanisms in multiply relapsed pediatric acute lymphoblastic leukemia

Area of Science:

• Genetics
• Oncology
• Genomics

Background:

• Pediatric acute lymphoblastic leukemia (ALL) typically has low mutational burden at diagnosis.
• This mutational load significantly increases upon relapse, suggesting evolving genomic instability.
• Understanding these mutational processes is crucial for managing relapsed disease.

Purpose of the Study:

• To investigate the mutational processes active in relapsed pediatric ALL.
• To analyze how these processes change during disease progression before and after therapy.
• To identify key drivers of mutagenesis in multiply relapsed ALL patients.

Main Methods:

• Whole genome sequencing was performed on 97 tumor samples from 29 multiply relapsed pediatric ALL patients.
• Analysis focused on identifying and characterizing distinct mutational signatures.
• Correlation of mutational processes with clinical data, including thiopurine exposure.

Main Results:

• Mutational load increased significantly in 28 out of 29 patients upon relapse, and in 22 patients upon subsequent relapses.
• Identified mutational processes include UV-like damage, APOBEC activity, reactive oxygen species, thiopurine-associated damage, and an unknown therapy-related factor.
• Thiopurine exposure was a major source of new mutations in relapsed ALL, identified in over half the patients and linked to relapse-driving mutations.

Conclusions:

• Multiple mutational processes operate in parallel and dynamically during pediatric ALL development and progression.
• Thiopurine therapy is a significant contributor to mutagenesis in relapsed ALL.
• These findings highlight the complex genomic landscape of relapsed ALL and potential therapeutic vulnerabilities.