Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia

Adam J. de Smith, Juhi Ojha, Stephen S. Francis, Erica Sanders, Alyson A. Endicott, Helen M. Hansen, Ivan Smirnov, Amanda M. Termuhlen, Kyle M. Walsh, Catherine Metayer, Joseph L. Wiemels

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)72733-72745
Number of pages13
JournalOncotarget
Volume7
Issue number45
DOIs
StatePublished - 2016

Keywords

  • DOT1L
  • High hyperdiploid acute lymphoblastic leukemia
  • Microclonal mutations
  • Targeted deep-sequencing
  • Tumor heterogeneity

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    de Smith, A. J., Ojha, J., Francis, S. S., Sanders, E., Endicott, A. A., Hansen, H. M., Smirnov, I., Termuhlen, A. M., Walsh, K. M., Metayer, C., & Wiemels, J. L. (2016). Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia. Oncotarget, 7(45), 72733-72745. https://doi.org/10.18632/oncotarget.12238