Clonal origins of ETV6-RUNX1⁺ acute lymphoblastic leukemia: studies in monozygotic twins.
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.
1] Centre for Evolution and Cancer, The Institute of Cancer Research-London, London, UK [2] Department of Pathology, University of Pecs, Pecs, Hungary.
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Alpar
Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research-London, London, UK.
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D
Wren
Centre for Geogenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen K, Denmark.
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L
Ermini
1] Centre for Evolution and Cancer, The Institute of Cancer Research-London, London, UK [2] Pediatric Hematology-Oncology Program, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
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Mansur
Centre for Evolution and Cancer, The Institute of Cancer Research-London, London, UK.
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van Delft
Centre for Evolution and Cancer, The Institute of Cancer Research-London, London, UK.
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CM
Bateman
Centre for Evolution and Cancer, The Institute of Cancer Research-London, London, UK.
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Titley
Centre for Evolution and Cancer, The Institute of Cancer Research-London, London, UK.
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Kearney
Department of Pediatric Hematology and Oncology, Zabrze, Medical University of Silesia, Katowice, Poland.
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Szczepanski
Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research-London, London, UK.
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Gonzalez
Centre for Evolution and Cancer, The Institute of Cancer Research-London, London, UK.
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Ford
Centre for Evolution and Cancer, The Institute of Cancer Research-London, London, UK.
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NE
Potter
Centre for Evolution and Cancer, The Institute of Cancer Research-London, London, UK.
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Greaves
D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D019070:Cell Lineage / Q000235:genetics; D002999:Clone Cells; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005333:Fetus; D015973:Gene Expression Regulation, Leukemic; D015329:Gene Rearrangement, T-Lymphocyte; D006801:Humans; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism / Q000473:pathology*; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D014430:Twins, Monozygotic / Q000235:genetics*; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D011961:Receptors, Fc; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein