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The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias
Anna K Andersson1, Jing Ma2, Jianmin Wang3
11] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Clinical Genetics, Lund University, Lund, Sweden.
Abstract:
Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.
Insights
Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) shows few mutations, primarily affecting the PI3K-RAS pathway. Older children with MLL-R leukemia have more mutations, including epigenetic regulators.
Area of Science:
- Genomics
- Pediatric Oncology
- Molecular Biology
Background:
- Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) is a distinct subtype with a poor prognosis.
- Understanding the genetic underpinnings of infant MLL-R ALL is crucial for developing targeted therapies.
Purpose of the Study:
- To define the mutational landscape of infant MLL-R ALL.
- To compare the genomic profiles of infant MLL-R ALL with non-MLL-R infant ALL and MLL-R leukemia in older children.
Main Methods:
- Whole-genome, exome, RNA, and targeted DNA sequencing were performed on infant and older child leukemia samples.
- Comparative genomic analysis was conducted to identify somatic mutations and their frequencies.
Main Results:
- Infant MLL-R ALL exhibits an exceptionally low frequency of somatic mutations (mean 1.3 per case).
- Activating mutations in the kinase-PI3K-RAS signaling pathway were found in 47% of infant cases, often subclonal and lost at relapse.
- MLL-R leukemia in older children had significantly more somatic mutations (mean 6.5 per case) and frequent mutations in epigenetic regulators (45%).
Conclusions:
- Infant MLL-R ALL is characterized by a paucity of mutations, with PI3K-RAS pathway alterations being a key feature.
- The distinct mutational landscape of infant MLL-R ALL compared to older children suggests different pathogenic mechanisms and potential therapeutic vulnerabilities.
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