The myb genes as a target for anticancer therapy

Three members of myb gene family (a-, b- and c-myb) encode transcription factors. These proteins display a high degree of homology within their DNA-binding domain, and play the key role in cell cycle progression, differentiation and survival. The b-Myb
protein is expressed in all dividing cells, in contrary the expression of
a-Myb and c-Myb appears to be rather tissue specific. The b-Myb and c-Myb expression being induced within the G1 phase of the cell cycle and persisting at maximal levels through S phase. Inhibition of these proteins synthesis by treatment of cells with antisense oligonucleotides indicates that both transcription factors are required for transition from the G1 to S phase of the cell cycle. Expression of a-Myb shows no correlation with cell cycling, implying that it has no direct role in the cell proliferation. The normal c-myb protooncogene is expressed at high levels in immature hematopoietic cells, and decrease its expression is related to terminal differentiation. The different patterns of expression of c-myb and b-myb are exemplified by human progenitor cells. Generally, b-Myb may have a general role in cell proliferation, whereas c-Myb may have a specific role in differentiation. Overexpression of myb genes is presented in many hematological malignancies and cancers. Therefore, disruption of myb functions seem to be a promising strategy for the treatment of human malignancies. In this work, the results of in vitro and in vivo including clinical studies will be discussed. In chronic myelogenous leukaemia, antisense oligonucleotides against c-myb were used in ex vivo to purging before autologous bone marrow transplantation, and also in systemic treatment for blast crisis patients. The same or similar antisense oligonucleotides were tested in cell cultures and animal models of other leukaemias, melanoma, brain tumours, and colon cancer. The progress is moot to use novel modalities following as: 1) enhancing anti-myb drugs activity by modification of their structure and delivery to the target cells, 2) better understanding of the role of the particulary myb genes in human cancer,
3) explanation of relations between their abnormal function and drug resistance.