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.
The C-Myb transcription factor is essential for 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 2 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-based comparative genomic hybridization (array-CGH) identified short somatic duplications that include C-MYB (MYB(dup), n = 13 cases of 84 T-ALL, 15%). Expression analysis, including allele-specific approaches, showed stronger C-MYB expression in the MYB-rearranged cases compared with 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 down-regulate 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) and with a proliferation/mitosis expression signature. By contrast, the MYB(dup) alteration was associated with the previously defined T-ALL subtypes.
Clappier
Emmanuelle
E
Genome Rearrangements and Cancer Group, Institut National de la Santé et de la Recherche Médicale U728 and Institut Universitaire d'Hématologie, Paris 7 University, Hôpital Saint-Louis, Paris, France.
Cuccuini
Wendy
W
Kalota
Anna
A
Crinquette
Antoine
A
Cayuela
Jean-Michel
JM
Dik
Willem A
WA
Langerak
Anton W
AW
Montpellier
Bertrand
B
Nadel
Bertrand
B
Walrafen
Pierre
P
Delattre
Olivier
O
Aurias
Alain
A
Leblanc
Thierry
T
Dombret
Hervé
H
Gewirtz
Alan M
AM
Baruchel
André
A
Sigaux
Francois
F
Soulier
Jean
J
D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000368:Aged; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D007223:Infant; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D014178:Translocation, Genetic
D020598:Proto-Oncogene Proteins c-myb