MYB oncoproteins: emerging players and potential therapeutic targets in human cancer

Abstract

MYB transcription factors are highly conserved from plants to vertebrates, indicating that their functions embrace fundamental mechanisms in the biology of cells and organisms. In humans, the MYB gene family is composed of three members: MYB, MYBL1 and MYBL2, encoding the transcription factors MYB, MYBL1, and MYBL2 (also known as c-MYB, A-MYB, and B-MYB), respectively. A truncated version of MYB, the prototype member of the MYB family, was originally identified as the product of the retroviral oncogene v-myb, which causes leukaemia in birds. This led to the hypothesis that aberrant activation of vertebrate MYB could also cause cancer. Despite more than three decades have elapsed since the isolation of v-myb, only recently investigators were able to detect MYB genes rearrangements and mutations, smoking gun evidence of the involvement of MYB family members in human cancer. In this review, we will highlight studies linking the activity of MYB family members to human malignancies and experimental therapeutic interventions tailored for MYB-expressing cancers.

Fig. 1. MYB family members’ protein structures.

The v-myb DNA-binding domain is equivalent to amino acids 72–192 of MYB, except the introduction of four point mutations (I91N, L106H, V117D, and I181V) and the addition of six amino acids in N-terminal region derived from the retroviral Gag polyprotein. The white dots on AMV v-myb structure indicate point mutations important for the ability of v-myb to transform cells. MYB co-activators are listed in green and the co-repressors are listed in red. The DNA-binding domain (DBD) is comprised of three repeats (R1, R2, and R3). It is the binding site for a number of proteins including p100, PARP, c-Ski, N-CoR, RAR, Cyp40, C/EMPbeta, SMRT, and mSin3A, as depicted; the central transactivation domain (TAD) is the interaction site for CBP/p300; the negative regulatory domain (NRD) extends from the FAETL motif to the EVES peptide sequence (involved in intramolecular and intermolecular protein–protein interactions) and includes the binding sites for p160/p67, Pin1, and TIF1beta^,–. The post-translational modifications include phosphorylation (P), acetylation (AC), and sumoylation (SUMO)^–.

Fig. 2. Schematic illustration of the MYB-NFIB fusion gene.

The t(6;9) translocation results in a MYB-NFIB gene fusion. Arrows indicate the breaking points.