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Oncogenes

CALM-AF10+ T-ALL expression profiles are characterized by overexpression of HOXA and BMI1 oncogenes

Leukemia volume 19, pages 1948–1957 (2005)Cite this article

Abstract

The t(10;11)(p13;q14–21) is found in T-ALL and acute myeloid leukemia and fuses CALM (Clathrin-Assembly protein-like Lymphoid-Myeloid leukaemia gene) to AF10. In order to gain insight into the transcriptional consequences of this fusion, microarray-based comparison of CALM-AF10+ vs CALM-AF10− T-ALL was performed. This analysis showed upregulation of HOXA5, HOXA9, HOXA10 and BMI1 in the CALM-AF10+ cases. Microarray results were validated by quantitative RT-PCR on an independent group of T-ALL and compared to mixed lineage leukemia-translocated acute leukemias (MLL-t AL). The overexpression of HOXA genes was associated with overexpression of its cofactor MEIS1 in CALM-AF10+ T-ALL, reaching levels of expression similar to those observed in MLL-t AL. Consequently, CALM-AF10+ T-ALL and MLL-t AL share a specific HOXA overexpression, indicating they activate common oncogenic pathways. In addition, BMI1, located close to AF10 breakpoint, was overexpressed only in CALM-AF10+ T-ALL and not in MLL-t AL. BMI1 controls cellular proliferation through suppression of the tumor suppressors encoded by the CDKN2A locus. This locus, often deleted in T-ALL, was conserved in CALM-AF10+ T-ALL. This suggests that decreased CDKN2A activity, as a result of BMI1 overexpression, contributes to leukemogenesis in CALM-AF10+ T-ALL. We propose to define a HOXA+ leukemia group composed of at least MLL-t, CALM-AF10 and HOXA-t AL, which may benefit from adapted management.

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Acknowledgements

ED is supported by Fondation de France, Comité Leucémie, l'Association de Recherche contre le Cancer et la Ligue Nationale contre le Cancer, comité de Paris. WAD, JJMvD and AWL are supported by the Dutch Cancer Foundation (EMCR 2002-2707), AWL is supported in part by the Haak Bastiaanse Kuneman Foundation. We thank Dr Frank JT Staal from the Department of Immunology, Erasmus MC, Rotterdam, for technical advice on microarray analysis, Dr Jean-Philippe Jais from the Department of Biostatistics, Hôpital Necker-Enfants-Malades, for statistical support, Dr Jean-Michel Cayuela from the Laboratory of Hematology, Hôpital Saint-Louis, Paris, for the gift of CDKN2A probe and Pr Ali Saad from the Laboratory of Cytogenetics, Farhat Hached hospital, Sousse, Tunisia, for valuable help.

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  1. W A Dik and W Brahim: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Immunology, Erasmus MC, Rotterdam, The Netherlands

    W A Dik, J J M van Dongen & A W Langerak

  2. Department of Hematology, Université Paris-Descartes, Faculté de Médecine, Hôpital Necker-Enfants-Malades, Paris, France

    W Brahim, C Braun, V Asnafi, E A Macintyre & E Delabesse

  3. INSERM EMI0210, Hôpital Necker-Enfants-Malades, Paris, France

    W Brahim, C Braun, V Asnafi, O A Bernard, E A Macintyre & E Delabesse

  4. Department of Hematology, Université Toulouse III Paul-Sabatier, Hôpital Purpan, Toulouse, France

    N Dastugue

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Dik, W., Brahim, W., Braun, C. et al. CALM-AF10+ T-ALL expression profiles are characterized by overexpression of HOXA and BMI1 oncogenes. Leukemia 19, 1948–1957 (2005). https://doi.org/10.1038/sj.leu.2403891

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