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

Abstract

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 downregulate C-MYB. Strikingly, profiling of the T-ALLs by clinical, genomic, and largescale 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. (Blood.

A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability

“…This is surprising because there is generally strong correlation between transactivation and transformation by c-Myb (Hu et al, 1991), and the importance of functional co-activation by CBP/p300 (Pattabiraman et al, 2009) and menin/MLL (Jin et al, 2010) has been shown. In cancers linked to aberrations involving the MYB locus, increased c-Myb dosage, and hence activity, seems to be a common theme (Clappier et al, 2007;Lahortiga et al, 2007;Persson et al, 2009). Nevertheless, the 2KR and ANAA mutants described here seem to partially dissociate transactivation from transformation.…”

“…The MYB locus is rearranged in several human neoplasias, with increased expression as a frequent outcome. This can be caused by translocation, leading to deregulation of the MYB gene, as in childhood T-cell acute lymphoblastic leukemia (Clappier et al, 2007), or stabilization of MYB mRNA, as in adenoid cystic carcinomas of the breast, head and neck (Persson et al, 2009). Local duplication of MYB has also been reported with another subgroup of T-cell acute lymphoblastic leukemia (Clappier et al, 2007;Lahortiga et al, 2007) and in a subgroup of acute myelomonocytic leukemia (Murati et al, 2009).…”

Mutations in Multiple Domains of c-Myb Disrupt Interaction with CBP/p300 and Abrogate Myeloid Transforming Ability

“…Although isolated cases of amplification and truncation of MYB have also been described some time ago in human leukemias (8,9), the use of newer, higher-resolution genomic technologies is suggesting that MYB contributes more frequently to these diseases. Thus, chromosomal translocation and genomic duplications of MYB have been identified in human T-cell acute leukemia (10,11); more recently, a gain of the MYB locus has been reported in acute myelomonocytic leukemia (12).…”

MYB IS Required for B-Selection During Thymopoises

“…However, expression is also detected in smooth muscle cells [199], gut epithelium [200], hair follicles [201] and several non-hematopoietic carcinomas such as small cell lung carcinoma [202], colon carcinoma [203], breast carcinoma [204], and neuroblastoma [205], as well as Tcell acute lymphoblastic leukemia [206,207]. Interestingly, expression of Myb mRNA is abundantly expressed in hematopoietic progenitor cells and expression decreases as cells approach terminal differentiation [194,[208][209][210].…”

“…Gene duplication of Myb or translocation of the Myb locus into the Tcrb locus is detected in patients with T-cell acute lymphoblastic leukemia (T-ALL), a neoplastic disorder of progenitor T cells [206,207]. The Myb-Tcrb translocation, which defines a new subset of T-ALL, places Myb expression under the control of Tcrb regulatory elements suggesting that continuous expression of c-Myb during thymopoiesis had an adverse effect characterized by increased expression of genes involved in cellular proliferation [206]. Together this data demonstrated that regulation of Myb expression is crucial during thymopoiesis;…”