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  • Original Article
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Cytogenetics and Molecular Genetics

DNA copy-number abnormalities do not occur in infant ALL with t(4;11)/MLL-AF4

Leukemia volume 24, pages 169–176 (2010)Cite this article

Abstract

The pathogenesis of infant acute lymphoblastic leukemia (ALL) is still not well defined. Short latency to leukemia and very high concordance rate for ALL in Mixed-Lineage Leukemia (MLL)-positive infant twins suggest that the MLL rearrangement itself could be sufficient for overt leukemia. Attempts to generate a suitable mouse model for MLL-AF4-positive ALL did not thoroughly resolve the issue of whether cooperating mutations are required to reduce latency and to generate overt leukemia in vivo. In this study, we applied single-nucleotide polymorphism array technology to perform genomic profiling of 28 infant ALL cases carrying t(4;11) to detect MLL-cooperating aberrations hidden to conventional techniques and to gain new insights into infant ALL pathogenesis. In contrast to pediatric, adolescent and adult ALL cases, the MLL rearrangement in infant ALL is associated with an exceptionally low frequency of copy-number abnormalities, thus confirming the unique nature of this disease. By contrast, additional genetic aberrations are acquired at disease relapse. Small-segmental uniparental disomy traits were frequently detected, mostly constitutional, and widely distributed throughout the genome. It can be argued that the MLL rearrangement as a first hit, rather than inducing the acquisition of additional genetic lesions, has a major role to drive and hasten the onset of leukemia.

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Acknowledgements

We thank Tatiana Gorletta and Angela Papagna (‘Genopolis’ Consortium, University of Milan-Bicocca, Milan, Italy) for array hybridization. We are grateful to the Italian ‘Interfant Task Force’ and all Italian clinicians for collecting and sending patient samples. This study was partially supported by financial grants from FIRB-MIUR ‘Genopolis’ n.RBLA038RMA_005 and FIRB-MIUR n.RBLA03ER38; Associazione Italiana per la Ricerca sul Cancro (AIRC), grant n.4342_2006 (to GC) and 2690_2004/06 (to AB); the Italian Foundation for Cancer Research (FIRC) fellowship ‘David Raffaelli’ to MB, Grant Ric.Corrente OBG 2006/02/R/001822 (to GDR); Fondazione Cariplo, Fondazione ‘M.Tettamanti’-Monza and Fondazione ‘Città della Speranza’-Padova. GC designed the research and supervised the contribution of all the authors; MB performed the research and wrote the paper, with support of GC; RS, SB, EM, IC, and CB conducted the SNP array analyses and contributed to the writing of the paper. LC and GF performed additional molecular screenings, MG performed gene expression analysis, GB is responsible of the National cell bank and conducted FISH screening, GDR and AB are the National responsible of the Interfant protocol.

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Authors and Affiliations

  1. Centro Ricerca Tettamanti, Clinica Pediatrica Univ. Milano-Bicocca, Monza, Italy

    M Bardini, S Bungaro, L Corral, G Fazio, A Biondi & G Cazzaniga

  2. International PhD in Molecular Medicine, Università Vita-Salute San Raffaele, Milano, Italy

    M Bardini

  3. Proteomics and Metabolomics Unit, Istituto di Tecnologie Biomediche-Segrate, Consiglio Nazionale delle Ricerche, Milano, Italy

    R Spinelli & I Cifola

  4. Centro Interdisciplinare Studi Bio-molecolari e Applicazioni Industriali (CISI), Università degli Studi di Milano, Milano, Italy

    E Mangano & C Battaglia

  5. Dipartimento di Scienze e Tecnologie Biomediche (DiSTeB) and Scuola di Dottorato di Medicina Molecolare, Università degli Studi di Milano, Milano, Italy

    E Mangano & C Battaglia

  6. Laboratorio di Emato-Oncologia, Clinica Pediatrica Università di Padova, Padova, Italy

    M Giordan & G Basso

  7. Divisione di Ematologia, Ospedale Pediatrico Bambino Gesù, Città del Vaticano, Roma, Italy

    G De Rossi

Authors
  1. M Bardini
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  2. R Spinelli
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  3. S Bungaro
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  4. E Mangano
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  5. L Corral
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  6. I Cifola
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  7. G Fazio
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  8. M Giordan
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  9. G Basso
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  10. G De Rossi
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  11. A Biondi
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Corresponding author

Correspondence to A Biondi.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Bardini, M., Spinelli, R., Bungaro, S. et al. DNA copy-number abnormalities do not occur in infant ALL with t(4;11)/MLL-AF4. Leukemia 24, 169–176 (2010). https://doi.org/10.1038/leu.2009.203

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  • DOI: https://doi.org/10.1038/leu.2009.203

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