| |  |
| |
| Description | The MYB protein consists of three distinct functional domains: an N-terminal helix-turn-helix (HTH)-type DNA binding domain (DBD), a centrally located trans-activation domain (TAD) and a C-terminal negative regulatory domain (NRD).
The DBD consists of three tandem 52 amino acid repeat termed R1, R2 and R3, which are involved in recognition and binding to the consensus sequence PyAACT/GG, known as the MYB binding site (MBS). MYB's trans-activation of its target genes requires the TAD. The NRD negatively regulates the trans-activating and transforming capacity of MYB. Several motifs within the NRD have been identified, including a Heptad Leucine Repeat (HLR) and a highly conserved EVES motif. Disruption of the HLR motif results in enhancement of MYB's trans-activating and transforming capacities. The EVES motif is also involved in negative regulation of MYB's activity by mediating interactions between the N-terminus and the C-terminus of the MYB protein.
MYB protein is subject to post-translational modifications, including ubiquitination, sumoylation, acetylation and phosphorylation. |
| Expression | MYB is expressed predominantly in immature progenitor cells of all haemopoietic lineages and these levels decrease as the cells progress towards terminal differentiation, although in differentiated T cells, MYB can be up-regulated upon activation.
Besides the haemopoietic system, MYB expression is also detected in colonic crypts and neurogenic niches.
MYB is highly expressed in almost all leukaemias. Overexpression of MYB is also detected in some solid tumors, such as breast cancer and colon cancer. |
| Localisation | MYB is localized to the nucleus. |
| Function | MYB mostly operates as a transcriptional activator. It binds to its cognate binding site (MYB binding site MBS; consensus A/C A A C G/T G) on target genes and regulates their expression.
MYB is essential for the establishment of definitive haemopoiesis; as such, myb-/- mice die of anoxia by embryonic day 15. Conditional knockout mice have shown that myb is required at different stages of differentiation of the T and B lymphoid lineages. MYB is also reported to play a role in maintaining the haemopoietic stem cell pool. Interestingly, hypomorphic myb alleles result in an increase in platelet numbers in mouse models.
MYB is involved in maintaining the proliferation of progenitor cells. Knockdown of MYB in leukaemic cells and estrogen receptor positive breast cancer cells, where it is highly expressed, significantly slows down cell proliferation. Overexpressed or activated MYB suppresses normal differentiation and promotes leukaemic transformation. However, MYB also activates a number of haemopoietic-specific genes. |
| Homology | The MYB gene family contains the other two closely related members, MYBL1 (also known as A-MYB) and MYBL2 (also known as B-MYB).
The DBD is highly conserved between mammalian, chicken and drosophila MYB proteins, as well as MYBL1 and MYBL2. The MYB DBD also shares homology with other proteins, such as telomeric repeat binding factor -1, -2 (TRF1, TRF2) and cyclin D binding myb-like transcription factor 1 (DMTF1). |
| Entity | T-cell acute lymphoblastic leukaemia |
| Disease | Translocation involving MYB and the T-cell receptor beta (TCRbeta) locus t(6;7)(q23;q34) and somatic genomic duplications at the C-MYB locus. |
| Cytogenetics | Molecular mapping of the chromosomal breakpoints show 2 discrete breakpoint clusters at 6q23.3: One located 5kb telomeric, 3' of the C-MYB gene, and the other 50kb more telomeric. Another gene (AHI1) was located in the vicinity of the t(6;7) breakpoints and was disrupted in some cases. In all cases, the translocation placed C-MYB in the vicinity of the TCRbeta regulatory sequence. |
| Oncogenesis | The abnormal regulation of C-MYB expression in this case confers a block of differentiation and continued proliferative capacity leading to its oncogenicity. |
| | |
| Entity | Acute myeloid leukaemia |
| Note | MYB is over-expressed in most human acute myeloid and lymphoid leukaemias. Several studies using antisense oligonucleotides and dominant negative forms of MYB have shown that MYB activity is essential for continued proliferation of AML and CML cells. Also, AML and CML cells are more sensitive to inhibition of MYB than their normal counterparts. |
| | |
| Entity | AML that have MYST3-linked abnormalities |
| Disease | Genomic gain of the MYB locus. |
| Prognosis | MYST3-linked AMLs have been shown to be associated with poor prognosis. |
| Oncogenesis | A gain of the MYB locus at 6q23 was recurrently detected in AMLs that have MYST3-translocations. A consequent increase in MYB mRNA levels was also reported. |
| | |
| Entity | Colorectal cancer |
| Prognosis | MYB is over-expressed in >80% of colorectal cancers. MYB expression correlates with poor prognosis for patients with colorectal cancer. |
| Oncogenesis | Robust mRNA expression and MYB mRNA amplifications were identified in colorectal cancer cell lines. Protein overexpression is a feature of these cell lines and primary cancers. Mutations in the first intron of MYB in the Atn region that regulates transcriptional elongation have been reported in some colorectal cancer cell lines and primary cancers. |
| | |
| Entity | Breast cancers |
| Note | MYB over-expression. |
| Prognosis | Since Myb over-expression is closely related to estrogen receptor positivity in breast cancers, prognosis is generally positive. This is due to the less severe nature of ER+ breast tumours and the availability of established therapeutics. |
| Oncogenesis | 64% of breast cancers express MYB, which also strongly correlates with ERalpha positivity. |
| | |
| Entity | Breast cancer harboring BRCA1 mutations |
| Note | MYB amplification is seen in 29% of tumours in women with BRCA1 mutations. |
| Disease | MYB amplification. |
| | |
| Three new types of viral oncogene of cellular origin specific for haematopoietic cell transformation. |
| Roussel M, Saule S, Lagrou C, Rommens C, Beug H, Graf T, Stehelin D. |
| Nature. 1979 Oct 11;281(5731):452-5. |
| PMID 226888 |
| |
| Expression of cellular homologues of retroviral onc genes in human hematopoietic cells. |
| Westin EH, Wong-Staal F, Gelmann EP, Dalla-Favera R, Papas TS, Lautenberger JA, Eva A, Reddy EP, Tronick SR, Aaronson SA, Gallo RC. |
| Proc Natl Acad Sci U S A. 1982 Apr;79(8):2490-4. |
| PMID 6283530 |
| |
| Viral myb oncogene encodes a sequence-specific DNA-binding activity. |
| Biedenkapp H, Borgmeyer U, Sippel AE, Klempnauer KH. |
| Nature. 1988 Oct 27;335(6193):835-7. |
| PMID 3185713 |
| |
| Delineation of three functional domains of the transcriptional activator encoded by the c-myb protooncogene. |
| Sakura H, Kanei-Ishii C, Nagase T, Nakagoshi H, Gonda TJ, Ishii S. |
| Proc Natl Acad Sci U S A. 1989 Aug;86(15):5758-62. |
| PMID 2668947 |
| |
| Strong association between c-myb and oestrogen-receptor expression in human breast cancer. |
| Guerin M, Sheng ZM, Andrieu N, Riou G. |
| Oncogene. 1990 Jan;5(1):131-5. |
| PMID 2181374 |
| |
| How can oncogenic transcription factors cause cancer: a critical review of the myb story. |
| Introna M, Golay J. |
| Leukemia. 1999 Sep;13(9):1301-6. (REVIEW) |
| PMID 10482978 |
| |
| MYB oncogene amplification in hereditary BRCA1 breast cancer. |
| Kauraniemi P, Hedenfalk I, Persson K, Duggan DJ, Tanner M, Johannsson O, Olsson H, Trent JM, Isola J, Borg A. |
| Cancer Res. 2000 Oct 1;60(19):5323-8. |
| PMID 11034064 |
| |
| Suppressor screen in Mpl-/- mice: c-Myb mutation causes supraphysiological production of platelets in the absence of thrombopoietin signaling. |
| Carpinelli MR, Hilton DJ, Metcalf D, Antonchuk JL, Hyland CD, Mifsud SL, Di Rago L, Hilton AA, Willson TA, Roberts AW, Ramsay RG, Nicola NA, Alexander WS. |
| Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6553-8. Epub 2004 Apr 7. |
| PMID 15071178 |
| |
| c-Myb and p300 regulate hematopoietic stem cell proliferation and differentiation. |
| Sandberg ML, Sutton SE, Pletcher MT, Wiltshire T, Tarantino LM, Hogenesch JB, Cooke MP. |
| Dev Cell. 2005 Feb;8(2):153-66. |
| PMID 15691758 |
| |
| Mutations in the MYB intron I regulatory sequence increase transcription in colon cancers. |
| Hugo H, Cures A, Suraweera N, Drabsch Y, Purcell D, Mantamadiotis T, Phillips W, Dobrovic A, Zupi G, Gonda TJ, Iacopetta B, Ramsay RG. |
| Genes Chromosomes Cancer. 2006 Dec;45(12):1143-54. |
| PMID 16977606 |
| |
| The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children. |
| Clappier E, Cuccuini W, Kalota A, Crinquette A, Cayuela JM, Dik WA, Langerak AW, Montpellier B, Nadel B, Walrafen P, Delattre O, Aurias A, Leblanc T, Dombret H, Gewirtz AM, Baruchel A, Sigaux F, Soulier J. |
| Blood. 2007 Aug 15;110(4):1251-61. Epub 2007 Apr 23. |
| PMID 17452517 |
| |
| Critical roles for c-Myb in hematopoietic progenitor cells. |
| Greig KT, Carotta S, Nutt SL. |
| Semin Immunol. 2008 Aug;20(4):247-56. Epub 2008 Jun 26. (REVIEW) |
| PMID 18585056 |
| |
| Alternative RNA splicing produces multiple forms of c-Myb with unique transcriptional activities. |
| O'Rourke JP, Ness SA. |
| Mol Cell Biol. 2008 Mar;28(6):2091-101. Epub 2008 Jan 14. |
| PMID 18195038 |
| |
| MYB function in normal and cancer cells. |
| Ramsay RG, Gonda TJ. |
| Nat Rev Cancer. 2008 Jul;8(7):523-34. (REVIEW) |
| PMID 18574464 |
| |
| Genome profiling of acute myelomonocytic leukemia: alteration of the MYB locus in MYST3-linked cases |
| Murati A, Gervais C, Carbuccia N, Finetti P, Cervera N, Adelaide J, Struski S, Lippert E, Mugneret F, Tigaud I, Penther D, Bastard C, Poppe B, Speleman F, Baranger L, Luquet I, Cornillet-Lefebvre P, Nadal N, Nguyen-Khac F, Perot C, Olschwang S, Bertucci F, Chaffanet M, Lessard M, Mozziconacci MJ, Birnbaum D; Groupe Francophone de Cytogenetique Hematologique. |
| Leukemia. 2009 Jan;23(1):85-94. Epub 2008 Sep 25. |
| PMID 18818702 |
| |
