A New Subtype of T-Cell Acute Leukemia in Very Young Children Is Defined by a Translocation Targeting the C-MYB Oncogene, and a Specific Gene Expression Signature.
Authors: Clappier Emmanuelle , Cuccuini Wendy , Kalota Anna , Crinquette Antoine , Cayuela Jean-Michel , Dik Willem A. , Langerak Anton W. , Montpellier Bertrand , Nadel Bertrand , Walrafen Pierre , Aurias Alain , Leblanc Thierry , Dombret Herve , Gewirtz Alan M. , Baruchel Andre , Sigaux Francois , Soulier Jean 
Published: October 2019

Cytogenetics and expression studies have pointed out an increasing number of oncogenes in T-cell acute lymphoblastic leukemias (T-ALL), demonstrating the complexity of T-ALL oncogenesis and the requirement for a network of cooperative genomic events. Here, we identified two types of genomic alterations involving the C-MYB locus at 6q23 in human T-ALL, both associated with transcriptional deregulation. First, using a TCRB-based FISH screening, we found a new reciprocal translocation, t(6;7)(q23;q34), that juxtaposed the TCRB and C-MYB loci (n=6 cases). Breakpoints were fully characterized at the molecular level in 3 cases. Second, a genome wide copy-number analysis by array-CGH (customized 4K BAC/PAC arrays) identified short cryptic duplications which always include the C-MYB gene (MYBdup, n=11 out of 80 primary pediatric and adult T-ALL, 14%). Somatic origin of the genomic gain was demonstrated using paired leukemic and remission samples. The minimal region of gain was mapped to 230 Kb using 244K oligonucleotide a-CGH, and fiber-FISH demonstrated tandem duplication. Interestingly, these genomic events are reminiscent of the frequent myb retroviral insertions in murine leukemia. Expression analysis by RQ-PCR and microarrays data showed stronger C-MYB expression in the MYB-rearranged cases compared to other T-ALLs and normal controls (thymus, BM, and PBL). Moreover, allele-specific approaches showed a dramatically skewed allele expression in the TCRB-MYB cases, suggesting that the translocation-driven deregulated expression overcomes a cellular attempt to downregulate C-MYB. Considering that the C-MYB transcription factor has been involved at several key steps throughout normal thymic differentiation, these data strongly suggest that deregulation of C-MYB due to genomic events is oncogenic in T-ALL. Integrated analysis of clinical, genomic, and large-scale gene expression data showed that the MYB translocation defines a new T-ALL subtype. Strikingly, 5 out of 6 patients with the translocation had a very young age for T-cell leukemia (1.1, 1.3, 1.8, 2.5, and 2.9 year-old; median 2.2 versus 9.4 year-old for 355 pediatric T-ALL in the FRALLE 93/2000 pediatric trials, p<10−4). Gene expression profiling showed that these cases cluster in a new branch distinct from other subtypes and are characterized by a specific cell cycle/mitosis signature. By contrast, the MYBdup alteration was associated to previously defined T-ALL subtypes (TAL, TLX1/HOX11, TLX3/HOX11L2, MLL, CALM-AF10, and immature cases), suggesting an additional oncogenic event. NOTCH1 activating mutations and p16/CDKN2A/ARF deletions were found in both the TCRB-MYB and MYBdup cases, according to multi-step T-cell oncogenesis. This work is the first clear demonstration of the recurrent involvement of the C-MYB locus in a human neoplasia. Moreover the t(6;7) translocation defines a new T-ALL subtype associated with very young age for T-cell leukemia and a distinct biology.