New tricks from an old oncogene

Abstract

MYB is a leucine zipper transcription factor that is essential for hematopoesis and for renewal of colonic crypts. There is also ample evidence showing that MYB is leukemogenic in several animal species. However, it was not until recently that clear evidence was presented showing that MYB actually is an oncogene rearranged in human cancer. In a recent study, a novel mechanism of activation of MYB involving gene fusion was identified in carcinomas of the breast and head and neck. A t(6;9) translocation was shown to generate fusions between MYB and the transcription factor gene NFIB. The fusions consistently result in loss of the 3´-end of MYB, including several highly conserved target sites for microRNAs that negatively regulate MYB expression. Deletion of these target sites may disrupt the repression of MYB, leading to overexpression of MYB-NFIB transcripts and protein and to transcriptional activation of critical MYB target genes associated with apoptosis, cell cycle control, cell growth/angiogenesis, and cell adhesion. This study, together with previous and recent data showing rearrangements and copy number alterations of the MYB locus in T-cell leukemia and certain solid tumors, will be the main focus of this review.

Acknowledgements

This work was supported by the Swedish Cancer Society and the IngaBritt and Arne Lundberg Research Foundation. We thank Ulric Pedersen for help preparing the illustrations. The authors have declared that no competing interests exist.

Figures and Tables

Figure 1 Gene fusions in salivary gland tumors. (A) PLAG1- and HMGA2-fusions in pleomorphic adenomas. (B) MAML2- and POU5F1-fusions in mucoepidermoid carcinomas and Warthin's tumors (metaplastic variant). (C) ETV6-NTRK3 fusions in mammary analogue secretory carcinoma of salivary glands and (D) the recently identified novel MYB-NFIB fusion in adenoid cystic carcinoma.

Figure 2 Schematic illustration of the MYB and NFIB genes and of two MYB-NFIB fusion variants (coding exons are shown i darker red and blue colors) and the resulting fusion proteins. Translocation breakpoints are shown by vertical arrows and miRNA binding sites for miR-15a/16 and miR-150 in the 3′-UTR of MYB are indicated by asteriks. The alternatively spliced MYB exon 9a and NFIB exons 8a, 8b and 8c are indicated. DBD, DNA binding domain; TAD, transactivation domain; NRD, negative regulatory domain.

Figure 3 MYB-NFIB is a nuclear protein. (A) Immunostaining of the MYB-NFIB fusion protein in a translocation-positive ACC. Note the predominant nuclear staining of tumor cells whereas stromal cells are negative. (B) Chinese hamster embryo fibroblasts (CHEF/18 cells) and NIH-3T3 cells (inset) transfected with a MYB-NFIB-GFP expression construct. Nuclei are counterstained in blue with 4′,6′-diamidino-2′-phenylindole dihydrochloride (DAPI). Fluorescent cells were fixed on glass slides and imaged using a Zeiss LSM510 META confocal microscope system.

Figure 4 Confirmed MYB downstream target genes that are overexpressed in fusion-positive ACCs relative to normal salivary gland tissue.

Figure 5 Schematic illustration of the translocation breakpoint region on the der(6) marker chromosome generated by the t(6;7)(q23;q34) translocation in T-ALL. Note that this translocation, unlike the t(6;9) in ACC, does not result in a MYB gene fusion. cen, centromere; tel, telomere. Adapted from reference 60.