1. ¹Department of Immunology, Erasmus MC, Rotterdam, The Netherlands
2. ²Department of Hematology, Université Paris-Descartes, Faculté de Médecine, Hôpital Necker-Enfants-Malades, Paris, France
3. ³INSERM EMI0210, Hôpital Necker-Enfants-Malades, Paris, France
4. ⁴Department of Hematology, Université Toulouse III Paul-Sabatier, Hôpital Purpan, Toulouse, France

Correspondence: Dr E Delabesse, Laboratoire d'Hématologie and INSERM EMI 0210, Hôpital Necker 149-161, rue de Sèvres, 75743 Paris cedex 15, France. Fax : +33 1443 81745; E-mail: eric.delabesse@nck.aphp.fr

⁵These authors contributed equally to this work

Received 3 June 2005; Accepted 31 June 2005; Published online 18 August 2005.

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.