Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia.
Journal Article (Journal Article)
High hyperdiploidy (HD), the most common cytogenetic subtype of B-cell acute lymphoblastic leukemia (B-ALL), is largely curable but significant treatment-related morbidity warrants investigating the biology and identifying novel drug targets. Targeted deep-sequencing of 538 cancer-relevant genes was performed in 57 HD-ALL patients lacking overt KRAS and NRAS hotspot mutations and lacking common B-ALL deletions to enrich for discovery of novel driver genes. One-third of patients harbored damaging mutations in epigenetic regulatory genes, including the putative novel driver DOT1L (n=4). Receptor tyrosine kinase (RTK)/Ras/MAPK signaling pathway mutations were found in two-thirds of patients, including novel mutations in ROS1, which mediates phosphorylation of the PTPN11-encoded protein SHP2. Mutations in FLT3 significantly co-occurred with DOT1L (p=0.04), suggesting functional cooperation in leukemogenesis. We detected an extraordinary level of tumor heterogeneity, with microclonal (mutant allele fraction <0.10) KRAS, NRAS, FLT3, and/or PTPN11 hotspot mutations evident in 31/57 (54.4%) patients. Multiple KRAS and NRAS codon 12 and 13 microclonal mutations significantly co-occurred within tumor samples (p=4.8x10-4), suggesting ongoing formation of and selection for Ras-activating mutations. Future work is required to investigate whether tumor microheterogeneity impacts clinical outcome and to elucidate the functional consequences of epigenetic dysregulation in HD-ALL, potentially leading to novel therapeutic approaches.
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Duke Authors
Cited Authors
- de Smith, AJ; Ojha, J; Francis, SS; Sanders, E; Endicott, AA; Hansen, HM; Smirnov, I; Termuhlen, AM; Walsh, KM; Metayer, C; Wiemels, JL
Published Date
- November 8, 2016
Published In
Volume / Issue
- 7 / 45
Start / End Page
- 72733 - 72745
PubMed ID
- 27683039
Pubmed Central ID
- PMC5341940
Electronic International Standard Serial Number (EISSN)
- 1949-2553
Digital Object Identifier (DOI)
- 10.18632/oncotarget.12238
Language
- eng
Conference Location
- United States