Download Gene Section MYB (v-myb myeloblastosis viral oncogene homolog (avian))

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
MYB (v-myb myeloblastosis viral oncogene
homolog (avian))
Liang Zhao, Diwakar R Pattabiraman, Thomas J Gonda
Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Australia
(LZ, DRP, TJG)
Published in Atlas Database: February 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/MYBID41466ch6q23.html
DOI: 10.4267/2042/44658
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Transcription
Identity
Multiple splicing variants of ~2.9 to 3.6 kb encode a
series of MYB proteins with identical DNA binding
domains but unique C-terminal domains. The best
characterized MYB variant is p89 with additional exon
9B.
The first intron contains an elongation attenuation
region (Atn) which is important in regulating
transcription of MYB.
Other
names:
C-myb;
Cmyb;
OTTHUMP00000017258; c-myb; c-myb10A_CDS; cmyb13A_CDS; c-myb14A_CDS; c-myb8B_CDS; cmyb_CDS; efg
HGNC (Hugo): MYB
Location: 6q23.3
Local order: Centromere SGK1 - ALDH8A1 - HBS1L
- MYB - AHI1 - PDE7B - FAM54A telomere.
Protein
DNA/RNA
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 transactivation 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.
Note
MYB was identified as the cellular homologue of vmyb, an oncogene found in two avian retroviruses
(Avian Myeloblastosis Virus (AMV) and E26), which
induce myeloblastic leukaemia and a mixed
myeloid/erythroid leukaemia, respectively, in chickens.
Description
The MYB gene spans 37.85 kb on the long arm of
chromosome 6 and is transcribed in the centromere-totelomere orientation.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(1)
36
MYB (v-myb myeloblastosis viral oncogene homolog (avian))
Zhao L, et al.
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 modify-cations, including
ubiquitination,
sumoylation,
acetylation
and
phosphorylation.
Homology
Expression
T-cell acute lymphoblastic leukaemia
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.
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 break-points
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.
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).
Implicated in
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.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(1)
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.
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.
37
MYB (v-myb myeloblastosis viral oncogene homolog (avian))
Zhao L, et al.
Sakura H, Kanei-Ishii C, Nagase T, Nakagoshi H, Gonda TJ,
Ishii S. Delineation of three functional domains of the
transcriptional activator encoded by the c-myb protooncogene.
Proc Natl Acad Sci U S A. 1989 Aug;86(15):5758-62
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.
Guérin M, Sheng ZM, Andrieu N, Riou G. Strong association
between c-myb and oestrogen-receptor expression in human
breast cancer. Oncogene. 1990 Jan;5(1):131-5
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.
Introna M, Golay J. How can oncogenic transcription factors
cause cancer: a critical review of the myb story. Leukemia.
1999 Sep;13(9):1301-6
Breast cancers
Sandberg ML, Sutton SE, Pletcher MT, Wiltshire T, Tarantino
LM, Hogenesch JB, Cooke MP. c-Myb and p300 regulate
hematopoietic stem cell proliferation and differentiation. Dev
Cell. 2005 Feb;8(2):153-66
Kauraniemi P, Hedenfalk I, Persson K, Duggan DJ, Tanner M,
Johannsson O, Olsson H, Trent JM, Isola J, Borg A. MYB
oncogene amplification in hereditary BRCA1 breast cancer.
Cancer Res. 2000 Oct 1;60(19):5323-8
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. Suppressor screen in
Mpl-/- mice: c-Myb mutation causes supraphysiological
production of platelets in the absence of thrombopoietin
signaling. Proc Natl Acad Sci U S A. 2004 Apr
27;101(17):6553-8
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.
Hugo H, Cures A, Suraweera N, Drabsch Y, Purcell D,
Mantamadiotis T, Phillips W, Dobrovic A, Zupi G, Gonda TJ,
Iacopetta B, Ramsay RG. Mutations in the MYB intron I
regulatory sequence increase transcription in colon cancers.
Genes Chromosomes Cancer. 2006 Dec;45(12):1143-54
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. 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. Blood.
2007 Aug 15;110(4):1251-61
Breast cancer harboring BRCA1
mutations
Greig KT, Carotta S, Nutt SL. Critical roles for c-Myb in
hematopoietic progenitor cells. Semin Immunol. 2008
Aug;20(4):247-56
Note
MYB amplification is seen in 29% of tumours in
women with BRCA1 mutations.
Disease
MYB amplification.
O'Rourke JP, Ness SA. Alternative RNA splicing produces
multiple forms of c-Myb with unique transcriptional activities.
Mol Cell Biol. 2008 Mar;28(6):2091-101
Ramsay RG, Gonda TJ. MYB function in normal and cancer
cells. Nat Rev Cancer. 2008 Jul;8(7):523-34
References
Murati A, Gervais C, Carbuccia N, Finetti P, Cervera N,
Adélaïde 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, Pérot C,
Olschwang S, Bertucci F, Chaffanet M, Lessard M,
Mozziconacci MJ, Birnbaum D. Genome profiling of acute
myelomonocytic leukemia: alteration of the MYB locus in
MYST3-linked cases. Leukemia. 2009 Jan;23(1):85-94
Roussel M, Saule S, Lagrou C, Rommens C, Beug H, Graf T,
Stehelin D. Three new types of viral oncogene of cellular origin
specific for haematopoietic cell transformation. Nature. 1979
Oct 11;281(5731):452-5
Westin EH, Wong-Staal F, Gelmann EP, Dalla-Favera R,
Papas TS, Lautenberger JA, Eva A, Reddy EP, Tronick SR,
Aaronson SA, Gallo RC. Expression of cellular homologues of
retroviral onc genes in human hematopoietic cells. Proc Natl
Acad Sci U S A. 1982 Apr;79(8):2490-4
This article should be referenced as such:
Zhao L, Pattabiraman DR, Gonda TJ. MYB (v-myb
myeloblastosis viral oncogene homolog (avian)). Atlas Genet
Cytogenet Oncol Haematol. 2010; 14(1):36-38.
Biedenkapp H, Borgmeyer U, Sippel AE, Klempnauer KH. Viral
myb oncogene encodes a sequence-specific DNA-binding
activity. Nature. 1988 Oct 27;335(6193):835-7
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(1)
38