Key Points
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The MYB oncogene is associated with leukaemogenesis in several species including humans. MYB can be activated by overexpression or inappropriate expression, structural alteration and/or genomic rearrangements.
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MYB is clearly required in the bone marrow, colonic crypt and neurogenic niches as demonstrated when global or tissue-specific knockout mice were generated. Multiple cell types are affected and these contribute to the stem cell niches in these tissues.
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MYB transcription is tightly regulated by attenuation sequences that reside in the first intron and mutations in this region in colorectal cancer correlate with elevated MYB expression, a characteristic of most colorectal cancers. In breast cancer oestrogen receptor-α (ERα) relieves the attenuation allowing elevated MYB expression, a characteristic of most ERα+ breast cancers.
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Sub-optimal MYB function, either through protein changes or through heterozygous loss, compromises the ability to maintain tissue homeostasis when these tissues are subjected to stress. This might have clinical implications for treating patients with abnormal MYB function who would otherwise appear normal.
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Over 80 cellular targets of the MYB transcription factor have been identified that partly, but incompletely, explain the importance of MYB in development, cell survival, proliferation and homeostasis. When MYB is overexpressed or inappropriately activated, some of these, and perhaps additional target genes, contribute to the transforming capacity of MYB.
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Therapeutic interventions that target MYB in malignancy have been limited, but the observation that ERα+ breast cancer cells have elevated MYB indicates that targeting ERα-regulated gene expression might be efficacious. In addition, immunotherapy against MYB is now under investigation.
Abstract
The transcription factor MYB has a key role as a regulator of stem and progenitor cells in the bone marrow, colonic crypts and a neurogenic region of the adult brain. It is in these compartments that a deficit in MYB activity leads to severe or lethal phenotypes. As was predicted from its leukaemogenicity in several animal species, MYB has now been identified as an oncogene that is involved in some human leukaemias. Moreover, recent evidence has strengthened the case that MYB is activated in colon and breast cancer: a block to MYB expression is overcome by mutation of the regulatory machinery in the former disease and by oestrogen receptor-α (ERα) in the latter.
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Acknowledgements
This work has been supported by research grants to R.G.R. and T.G. from the National Health and Medical Research Council of Australia, the Cancer Council of Victoria and the Queensland Cancer Fund. R.G.R. is also a National Research Fellow of the NHMRC. We wish to thank members of our respective laboratories for their ongoing commitment to hard work and dedication to unravelling the mysteries of MYB in cancer. Finally, sincere thanks to the members of the MYB research community with whom we have travelled in our growing understanding of what was once 'only a retroviral oncogene' in chickens but is now a key player in both normal and cancer biology in humans.
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Glossary
- Hypomorphic mutants
-
Mostly partial loss of function mutants. These mutations are extraordinarily valuable as they allow sufficient gene function to generate viable animals but are defective enough to produce a phenotype.
- Haematopoiesis
-
Responsible for generating all the cell lineages of the blood system. In adult mammals it has two principal arms that build the myeloid and lymphoid compartments. The former is responsible for macrophages, platelets, red blood cells, neutrophils, eosinophils and basophils. B- and T-cell production falls into the domain of the lymphoid compartment.
- Transcriptional elongation
-
An essential component of gene transcription that involves the extended polymerization of ribonucleotides as a gene is transcribed. This occurs after transcription initiation and seems to be subject to regulation both at short distances from the transcription initiation sites and during elongation itself.
- Mismatch repair
-
A process that identifies nucleotide changes that differ from the parental DNA strand, and which restores the daughter sequence to the wild-type or parental sequence. Regions that contain stretches of mono- or dinucleotide repeats are particularly prone to mutation if cells are defective in a group of proteins that collectively govern the mismatch repair process.
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Ramsay, R., Gonda, T. MYB function in normal and cancer cells. Nat Rev Cancer 8, 523–534 (2008). https://doi.org/10.1038/nrc2439
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DOI: https://doi.org/10.1038/nrc2439
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