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


Submitted: 11 May 2015
Accepted: 26 May 2015
Published: 24 November 2015
Abstract Views: 2323
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Authors

  • 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 Å korić 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.
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.

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
General Pediatric Department, Head of the Department

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Ivanovski, I., Garavelli, L., Djurić, O., Ćirović, A., Škorić, D., & Ivanovski, P. I. (2015). Mitotic crossover promotes leukemogenesis in children born with TEL-AML1 via the generation of loss of heterozygosity at 12p. La Pediatria Medica E Chirurgica, 37(2). https://doi.org/10.4081/pmc.2015.112

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