The MYB proto-oncogene is one of the key regulators in haematopoiesis and leukemogenesis and acts by blocking differentiation, promoting proliferation and cell survival. Most leukaemias express high level of MYB mRNA and their proliferation is dependent on MYB expression. Previous research demonstrates that a putative stem-loop motif of MYB pre mRNA sequence, located at 1.7kb downstream of the transcription starting site, controls MYB transcriptional elongation in colon tumour and estrogen receptor positive breast tumours. It is also reported MYB transcription is blocked in the first intron in some leukaemia cell lines, yet the mechanism of its transcriptional regulation is not well understood.
We have uncovered diverse mechanisms of MYB transcriptional regulation in leukaemia differentiation and MLL-AF9 induced myeloid leukaemia. During the differentiation of leukaemia, the decrease of MYB expression is due to a block, at least temporarily, at a site in the first intron upstream of the stem-loop motif. However in MLL-AF9 driven myeloid leukaemia, MYB transcription is regulated at the promoter region. We also demonstrate that MYB transcription is directly regulated by MLL-AF9 fusion protein and is correlates with the dynamic transition of RNA pol II phosphorylation. MLL-fusion can stimulate the transcription of MYB and this stimulation requires CDK9. Moreover, MYB transcription is independent of H3K79 methylation mark, which is normally enriched in gene coding regions and ubiquitously coupled to gene transcriptional activity. Furthermore, MYB transcription can be suppressed by inhibiting transcription regulators CDK9 and Brd4 via small pharmaceutical molecules, while MYB expression has no response to the inhibition of DOT1L, a H3K79 methyltransferase.
Understanding the mechanism of MYB transcription regulation and identification of its vital transcription regulators may enable effective targeting of MYB expression which may in turn lead to potential therapies for myeloid leukaemia.