Clonal origins of ETV6-RUNX1⁺ acute lymphoblastic leukemia: studies in monozygotic twins.

D. Alpar, D. Wren, L. Ermini, M. B. Mansur, F. W. van Delft, C. M. Bateman, I. Titley, L. Kearney, T. Szczepanski, D. Gonzalez, A.M. Ford, N. E. Potter, M. Greaves

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Studies on twins with concordant acute lymphoblastic leukemia (ALL) have revealed that ETV6-RUNX1 gene fusion is a common, prenatal genetic event with other driver aberrations occurring subclonally and probably postnatally. The fetal cell type that is transformed by ETV6-RUNX1 is not identified by such studies or by the analysis of early B-cell lineage phenotype of derived progeny. Ongoing, clonal immunoglobulin (IG) and cross-lineage T-cell receptor (TCR) gene rearrangements are features of B-cell precursor leukemia and commence at the pro-B-cell stage of normal B-cell lineage development. We reasoned that shared clonal rearrangements of IG or TCR genes by concordant ALL in twins would be informative about the fetal cell type in which clonal advantage is elicited by ETV6-RUNX1. Five pairs of twins were analyzed for all varieties of IG and TCR gene rearrangements. All pairs showed identical incomplete or complete variable-diversity-joining junctions coupled with substantial, subclonal and divergent rearrangements. This pattern was endorsed by single-cell genetic scrutiny in one twin pair. Our data suggest that the pre-leukemic initiating function of ETV6-RUNX1 fusion is associated with clonal expansion early in the fetal B-cell lineage.
Original languageEnglish
Pages (from-to)839-846
Number of pages8
JournalLeukemia
Volume29
Early online date16 Jan 2015
DOIs
Publication statusPublished - 2015
Externally publishedYes

Keywords

  • B-Lymphocytes
  • Cell Lineage
  • Clone Cells
  • Core Binding Factor Alpha 2 Subunit
  • Female
  • Fetus
  • Gene Expression Regulation, Leukemic
  • Gene Rearrangement, T-Lymphocyte
  • Humans
  • Male
  • Oncogene Proteins, Fusion
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Precursor Cells, B-Lymphoid
  • Receptors, Fc
  • T-Lymphocytes
  • Time Factors
  • Twins, Monozygotic

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    Alpar, D., Wren, D., Ermini, L., Mansur, M. B., van Delft, F. W., Bateman, C. M., Titley, I., Kearney, L., Szczepanski, T., Gonzalez, D., Ford, A. M., Potter, N. E., & Greaves, M. (2015). Clonal origins of ETV6-RUNX1⁺ acute lymphoblastic leukemia: studies in monozygotic twins. Leukemia, 29, 839-846. https://doi.org/10.1038/leu.2014.322