MYB (v-myb myeloblastosis viral oncogene homolog (avian))

2009-02-01   Liang Zhao , Diwakar R Pattabiraman , Thomas J Gonda 

Diamantina Institute for Cancer, Immunology, Metabolic Medicine, University of Queensland, Australia

Identity

HGNC
LOCATION
6q23.3
LOCUSID
ALIAS
Cmyb,c-myb,c-myb_CDS,efg
FUSION GENES

DNA/RNA

Note

MYB was identified as the cellular homologue of v-myb, 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.
Atlas Image

Description

The MYB gene spans 37.85 kb on the long arm of chromosome 6 and is transcribed in the centromere-to-telomere orientation.

Transcription

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.

Proteins

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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). MYBs 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 MYBs trans-activating and transforming capacities. The EVES motif is also involved in negative regulation of MYBs 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).

Implicated in

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.
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 name
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 name
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 name
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 name
Breast cancer harboring BRCA1 mutations
Note
MYB amplification is seen in 29% of tumours in women with BRCA1 mutations.
Disease
MYB amplification.

Breakpoints

Atlas Image

Bibliography

Pubmed IDLast YearTitleAuthors
31857131988Viral myb oncogene encodes a sequence-specific DNA-binding activity.Biedenkapp H et al
150711782004Suppressor screen in Mpl-/- mice: c-Myb mutation causes supraphysiological production of platelets in the absence of thrombopoietin signaling.Carpinelli MR et al
174525172007The 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 et al
185850562008Critical roles for c-Myb in hematopoietic progenitor cells.Greig KT et al
21813741990Strong association between c-myb and oestrogen-receptor expression in human breast cancer.Guérin M et al
169776062006Mutations in the MYB intron I regulatory sequence increase transcription in colon cancers.Hugo H et al
104829781999How can oncogenic transcription factors cause cancer: a critical review of the myb story.Introna M et al
110340642000MYB oncogene amplification in hereditary BRCA1 breast cancer.Kauraniemi P et al
188187022009Genome profiling of acute myelomonocytic leukemia: alteration of the MYB locus in MYST3-linked cases.Murati A et al
181950382008Alternative RNA splicing produces multiple forms of c-Myb with unique transcriptional activities.O'Rourke JP et al
185744642008MYB function in normal and cancer cells.Ramsay RG et al
2268881979Three new types of viral oncogene of cellular origin specific for haematopoietic cell transformation.Roussel M et al
26689471989Delineation of three functional domains of the transcriptional activator encoded by the c-myb protooncogene.Sakura H et al
156917582005c-Myb and p300 regulate hematopoietic stem cell proliferation and differentiation.Sandberg ML et al
62835301982Expression of cellular homologues of retroviral onc genes in human hematopoietic cells.Westin EH et al

Other Information

Locus ID:

NCBI: 4602
MIM: 189990
HGNC: 7545
Ensembl: ENSG00000118513

Variants:

dbSNP: 4602
ClinVar: 4602
TCGA: ENSG00000118513
COSMIC: MYB

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000118513ENST00000316528F8W8G5
ENSG00000118513ENST00000339290Q708E3
ENSG00000118513ENST00000341911P10242
ENSG00000118513ENST00000367812P10242
ENSG00000118513ENST00000367814P10242
ENSG00000118513ENST00000367814Q708E9
ENSG00000118513ENST00000420123E9PMQ0
ENSG00000118513ENST00000430686A0A0C4DG19
ENSG00000118513ENST00000438901E9PPL8
ENSG00000118513ENST00000442647P10242
ENSG00000118513ENST00000463282Q708E6
ENSG00000118513ENST00000524588E9PP87
ENSG00000118513ENST00000525002E9PJF1
ENSG00000118513ENST00000525369P10242
ENSG00000118513ENST00000525477P10242
ENSG00000118513ENST00000525477Q708E8
ENSG00000118513ENST00000525514P10242
ENSG00000118513ENST00000525514Q708E8
ENSG00000118513ENST00000525940E9PMZ0
ENSG00000118513ENST00000526187E9PNH6
ENSG00000118513ENST00000526320E9PMZ0
ENSG00000118513ENST00000526565Q708E6
ENSG00000118513ENST00000526889E9PKZ3
ENSG00000118513ENST00000527615E9PLN0
ENSG00000118513ENST00000528015E9PN43
ENSG00000118513ENST00000528140E9PN92
ENSG00000118513ENST00000528343E9PQQ2
ENSG00000118513ENST00000528345E9PJT2
ENSG00000118513ENST00000528774P10242
ENSG00000118513ENST00000529262E9PIW4
ENSG00000118513ENST00000529586P10242
ENSG00000118513ENST00000529586Q708E8
ENSG00000118513ENST00000531519E9PJ96
ENSG00000118513ENST00000531634E9PPR4
ENSG00000118513ENST00000531737E9PN92
ENSG00000118513ENST00000533384P10242
ENSG00000118513ENST00000533384Q708E5
ENSG00000118513ENST00000533624P10242
ENSG00000118513ENST00000533808P10242
ENSG00000118513ENST00000533808Q708E5
ENSG00000118513ENST00000533837P10242
ENSG00000118513ENST00000533837Q708E5
ENSG00000118513ENST00000534044P10242
ENSG00000118513ENST00000534121P10242
ENSG00000118513ENST00000534736H0YCN6
ENSG00000118513ENST00000616088A0A087WTI6
ENSG00000118513ENST00000618728Q708E1

Expression (GTEx)

0
5
10
15
20

Pathways

PathwaySourceExternal ID
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
HemostasisREACTOMER-HSA-109582
Factors involved in megakaryocyte development and platelet productionREACTOMER-HSA-983231

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
191986102009Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.271
191986102009Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.271
253947902014Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element.212
198412622009Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck.190
186676982008DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease.175
198620102009Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium.169
205314062010A human B-cell interactome identifies MYB and FOXM1 as master regulators of proliferation in germinal centers.155
223914502012The MuvB complex sequentially recruits B-Myb and FoxM1 to promote mitotic gene expression.121
174525172007The 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.93
174357592007Duplication of the MYB oncogene in T cell acute lymphoblastic leukemia.89

Citation

Liang Zhao ; Diwakar R Pattabiraman ; Thomas J Gonda

MYB (v-myb myeloblastosis viral oncogene homolog (avian))

Atlas Genet Cytogenet Oncol Haematol. 2009-02-01

Online version: http://atlasgeneticsoncology.org/gene/41466/myb