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Mitotic crossover promotes leukemogenesis in children born with TEL-AML1 via the generation of loss of heterozygosity at 12p

Ivan Ivanovski, Livia Garavelli, Olivera Djurić, Aleksandar Ćirović, Dejan Škorić, Petar I. Ivanovski
  • Ivan Ivanovski
    School of Medicine, University of Belgrade, Serbia; Struttura Semplice Dipartimentale di Genetica Clinica, Dipartimento Ostetrico-Ginecologico e Pediatrico, Istituto di Ricovero e Cura a Carattere Scientifico Arcispedale S. Maria Nuova, Reggio Emilia, Italy
  • Livia Garavelli
    Struttura Semplice Dipartimentale di Genetica Clinica, Dipartimento Ostetrico-Ginecologico e Pediatrico, Istituto di Ricovero e Cura a Carattere Scientifico Arcispedale S. Maria Nuova, Reggio Emilia, Italy
  • Olivera Djurić
    School of Medicine, University of Belgrade; Institute of Epidemiology, University of Belgrade, Serbia
  • Aleksandar Ćirović
    School of Medicine, University of Belgrade, Serbia
  • Dejan Škorić
    School of Medicine, University of Belgrade; Pediatric Clinic, University Children’s Hospital, Belgrade, Serbia
  • Petar I. Ivanovski
    School of Medicine, University of Belgrade; Pediatric Clinic, University Children’s Hospital, Belgrade, Serbia | ivanovsk@eunet.rs

Abstract

TEL-AML1 (ETV6-RUNX1) fusion gene which is formed prenatally in 1% of the newborns, is a common genetic abnormality in childhood Bcell precursor acute lymphoblastic leukemia. But only one child out of a hundred children born with this fusion gene develops leukemia (bottleneck phenomenon) later in its life, if contracts the second mutation. In other words, out of a hundred children born with TEL-AML1 only one child is at risk for leukemia development, which means that TEL-AML1 fusion gene is not sufficient for overt leukemia. There is a stringent requirement for a second genetic abnormality for leukemia development and this is the real or the ultimate cause of the leukemia bottleneck phenomenon. In most cases of TEL-AML1+ leukemia, the translocation t(12;21) is complemented with the loss of the normal TEL gene, not involved in the translocation, on the contralateral 12p. The loss of the normal TEL gene, i.e. loss of heterozygosity at 12p, occurs postnatally during the mitotic proliferation of TEL-AML1+ cell in the mitotic crossing over process. Mitotic crossing over is a very rare event with a frequency rate of 10–6 in a 10 kb region. The exploration and identification of the environmental exposure(s) that cause(s) proliferation of the TELAML1+ cell in which approximately 106 mitoses are generated to cause 12p loss of heterozygosity, i.e. TEL gene deletion, may contribute to the introduction of preventive measures for leukemia.

Keywords

TEL-AML1 fusion gene; Chromosomal translocation; 12p loss of heterozygosity; Mitotic cross over; Childhood acute lymphoblastic leukemia

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Submitted: 2015-05-11 17:17:59
Published: 2015-11-24 15:00:42
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Copyright (c) 2015 Ivan Ivanovski, Livia Garavelli, Olivera Djurić, Aleksandar Ćirović, Dejan Škorić, Petar I. Ivanovski

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