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Blood, 15 August 2007, Vol. 110, No. 4, pp. 1251-1261.
Prepublished online as a Blood First Edition Paper on April 23, 2007; DOI 10.1182/blood-2006-12-064683.
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Submitted December 26, 2006
Accepted April 19, 2007
The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL) - the translocation defining a new T-ALL subtype in very young children
Emmanuelle Clappier, Wendy Cuccuini, Anna Kalota, Antoine Crinquette, Jean-Michel Cayuela, Willem A Dik, Anton W Langerak, Bertrand Montpellier, Bertrand Nadel, Pierre Walrafen, Olivier Delattre, Alain Aurias, Thierry Leblanc, Herve Dombret, Alan M Gewirtz, Andre Baruchel, Francois Sigaux, and Jean Soulier*
Laboratoire de Biochimie Genetique, APHP, Hopital Robert Debre, Paris, France
Genome Rearrangements and Cancer Group, INSERM U728 and Institut Universitaire d'Hematologie, Paris 7 University, Hopital Saint-Louis, Paris, France
Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
Hematology Laboratory, APHP, Hopital Saint-Louis, Paris, France
Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, Netherlands
Centre d'immunologie de Marseille Luminy (CIML) INSERM-CNRS, Universite de la Mediterranee, Marseille, France
Genomic Vision, Institut Pasteur, Paris, France
Section Recherche, INSERM U509, Institut Curie, Paris, France
Pediatric Hematology Department, APHP, Hopital Saint-Louis, Paris, France
Adult Hematology Department, APHP, Hopital Saint-Louis, Paris, France
* Corresponding author; email: jean.soulier{at}sls.aphp.fr.
The c-Myb transcription factor is essential for primitive and adult hematopoiesis, including in the T-cell lineage. The c-myb locus is a common site of retroviral insertional mutagenesis, however no recurrent genomic involvement has been reported in human malignancies. Here, we identified two types of genomic alterations involving the C-MYB locus at 6q23 in human T-cell acute leukemia (T-ALL). First, we found a reciprocal translocation, t(6;7)(q23;q34), that juxtaposed the TCRB and C-MYB loci (n=6 cases). Second, a genome wide copy-number analysis by array-CGH identified short somatic duplications which include C-MYB (MYBdup, n=13 cases out of 84 T-ALL, 15%). Expression analysis, including allele-specific approaches, showed stronger C-MYB expression in the MYB-rearranged cases compared to other T-ALLs, and a dramatically skewed C-MYB allele expression in the TCRB-MYB cases which suggests that a translocation-driven deregulated expression may overcome a cellular attempt to downregulate C-MYB. Strikingly, profiling of the T-ALLs by clinical, genomic and large-scale gene expression analyses shows that the TCRB-MYB translocation defines a new T-ALL subtype associated with a very young age for T-cell leukemia (median 2.2 years-old) and with a proliferation/mitosis expression signature. By contrast, the MYBdup alteration was associated to the previously defined T-ALL subtypes.
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