Gene wiki reviewMYB – A regulatory factor in hematopoiesis
Introduction
v-MYB is an oncogene from avian myeloblastosis virus (AMV) (Hall et al., 1941) and E26 (another avian virus), implicated to be one of the oncogenes that cause myelomas and lymphomas in birds (Radke et al., 1982; Moscovici et al., 1983; Lipsick and Wang, 1999). c-MYB (MYB) was subsequently identified as a cellular homologue of the virus v-MYB (Klempnauer et al., 1982; Boyle et al., 1983; Klempnauer et al., 1983; Gonda et al., 1985; Majello et al., 1986) (Table 1). Other forms of MYB, A-MYB and B-MYB, exist in humans encoding transcription factors A-MYB and B-MYB, respectively, that share some homology, including the DNA binding domain, with c-MYB (Ganter and Lipsick, 1999; Bergholtz et al., 2001).
In this review MYB is used interchangeably with c-MYB and the encoded transcription factor referred to, as MYB. Since its discovery in the 1980s, MYB has been recognized as a crucial transcription factor in hematopoiesis and erythropoiesis. MYB is tightly regulated, deregulation of MYB is oncogenic; it has been shown to undergo rearrangement or translocation, leading to aberrant expression in human leukemias and lymphomas (Stenman et al., 2010; Pattabiraman and Gonda, 2013). MYB has also been shown to be highly expressed in colorectal, breast and pancreatic cancers (Biroccio et al., 2001; Persson et al., 2009). MYB has a critical physiological role in normal hematopoiesis; it is essential for definitive red cell maturation and its expression is precisely controlled during the different stages of hematopoiesis (Mucenski et al., 1991). More recently, studies have revealed that MYB has a role in regulating fetal hemoglobin gene expression (Jiang et al., 2006; Thein et al., 2007; Stadhouders et al., 2014), a major modifier of the severity of the beta hemoglobinopathies - beta thalassemia and sickle cell disease (Gardner and Thein, 2016; Thein, 2018).
While much has been learnt about MYB (see reviews, Ramsay and Gonda, 2008; Pattabiraman and Gonda, 2013; George and Ness, 2014; Paikari and Sheehan, 2018), a lot remains to be resolved about the regulatory control of MYB expression and how it impacts its function. MYB is considered as an oncogene, but the mechanism underlying this process is not clear. In some cancer cells, MYB expression is relatively higher, but it is not clear if the elevated expression is the cause of the oncogenic process. Forced over-expression of c-MYB did not cause the cells to become cancerous. Further, the key targeted gene(s) promoting oncogenesis regulated by MYB are still unknown, although many genes regulated by MYB have been investigated during differentiation, proliferation, apoptosis and development. While v-MYB and c-MYB have been studied for >3 decades, the structure of the whole protein is not known. Although functional dissection of MYB has revealed three domains - DNA binding domain (DBD), transcription activation domain (TAD), and negative regulatory domain (NRD)- (Fig. 1), the functional roles of these domains, especially TAD and NRD, have yet to be fully determined. For instance, it is not clear if the NRD is required for all of its role in oncogenesis, apoptosis, proliferation and differentiation. Notably, v-MYB lacks NRD in the C-terminus, which is not surprising that it functions as a transcriptional activator all the time, a property that likely contributes to its role in leukemogenesis.
Regulation of MYB expression is complex involving several levels, via its proximal promoter region (Sullivan et al., 1997) and microRNAs (miRNAs) at the posttranscriptional level (Lu et al., 2008; Zhao et al., 2009; Sankaran et al., 2011). Enforced miR-15a expression blocked both erythroid and myeloid colony formation in vitro, suggesting an important autoregulatory c-MYB-miR-15a circuit in human hematopoiesis (Zhao et al., 2009). A delayed HbF to HbA switch, along with persistently elevated HbF levels, in infants with trisomy 13 (Huehns et al., 1964) prompted further experiments that support involvement of miRNAs 15a and 16-1 in regulation of MYB expression. The gene encoding miRNAs 15a and 16-1 is localized on chromosome 13q14 that was unambiguously associated with the increased HbF trait in these infants (Sankaran et al., 2011). Recent experiments show that MYB is additionally controlled distally by enhancer elements >80 kb upstream of its promoter (Stadhouders et al., 2014) and mouse studies show that the activity of Myb takes place within an active chromatin hub (Stadhouders et al., 2012).
Section snippets
MYB proteins and its transcripts
c-MYB is a transcription factor which is vital for survival. It is predominantly expressed in immature hematopoietic cells, and its expression remains precisely controlled throughout development. Knockout of the gene results in lethality at day 14 of embryogenic stage in mouse (Mucenski et al., 1991; Vegiopoulos et al., 2006).
As for other transcription factors, MYB proteins are able to bind DNA. The consensus sequence for DNA binding is 5′-YAACG/TG -3 (Howe and Watson, 1991); (Bergholtz et al.,
MYB is an oncogene and it regulates cell proliferation and differentiation
Being a cellular counterpart of v-MYB, c-MYB has been labeled an oncogene. c-MYB is a common integration site for avian and murine retroviruses, leading to a variety of leukemias (Oh and Reddy, 1999; Ramsay and Gonda, 2008; Zhang et al., 2012). Further studies indicated that c-MYB may be associated with some epithelial cancers and even some neural carcinomas where c-MYB expression is relatively higher in the malignant cells. However, overexpression of full length c-MYB in animal cells do not
MYB is essential for hematopoiesis and red cell differentiation
MYB is a key regulator of hematopoiesis and erythropoiesis (Ramsay and Gonda, 2008); (Mucenski et al., 1991). c-MYB plays an essential role in controlling the erythroid cellular proliferation/differentiation balance (Vegiopoulos et al., 2006), sustains proliferation, and a low MYB environment favors accelerated differentiation (Emambokus et al., 2003).
RNA interference (RNAi) and gene knockout experiments provided evidence that c-MYB is essential for hematopoiesis. In earlier studies, Gewirtz
Summary
MYB is a transcription factor comprising 3 functional domains, DBD, TAD and NRD. It is required for hematopoiesis and essential for life. MYB can interact with many proteins, including p300, a multifunctional protein. p300 has several TAD domains and physically interact with many transcription factors. Both v-MYB and c-MYB are able to bind similar sequences of DNA and the functional difference may be from the protein interaction with other factors. Aberrant MYB expression, rare isoforms and
Acknowledgements
We thank Rusinel Amarante for her help in preparation of the manuscript.
Financial support and sponsorship
This work was supported by the Intramural Research Program of the National Heart, Lungs, and Blood Institute, NIH.
Conflicts of interest
None declared for all authors.
References (161)
- et al.
Revisiting a selection of target genes for the hematopoietic transcription factor c-Myb using chromatin immunoprecipitation and c-Myb knockdown
Blood Cells Mol. Dis.
(2007) - et al.
Covalent attachment of the SUMO-1 protein to the negative regulatory domain of the c-Myb transcription factor modifies its stability and transactivation capacity
J. Biol. Chem.
(2002) - et al.
c-Myb and Bcl-x overexpression predicts poor prognosis in colorectal cancer: clinical and experimental findings
Am. J. Pathol.
(2001) - et al.
Increased c-myb mRNA expression in Barrett's esophagus and Barrett's-associated adenocarcinoma
J. Surg. Res.
(2001) - et al.
Analysis of MYB expression and MYB-NFIB gene fusions in adenoid cystic carcinoma and other salivary neoplasms
Mod. Pathol.
(2011) - et al.
miR-150 regulates memory CD8 T cell differentiation via c-Myb
Cell Rep.
(2017) - et al.
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) - et al.
MYB-NFIB gene fusion in adenoid cystic carcinoma of the breast with special focus paid to the solid variant with basaloid features
Hum. Pathol.
(2014) - et al.
Study of the levels of expression of two oncogenes, c-myc and c-myb, in acute and chronic leukemias of both lymphoid and myeloid lineage
Leuk. Res.
(1985) - et al.
Myb and oncogenesis
Adv. Cancer Res.
(1999)
Whole-genome noncoding sequence analysis in T-cell acute lymphoblastic leukemia identifies oncogene enhancer mutations
Blood
Characterization of a rearrangement in the c-MYB promoter in the acute lymphoblastic leukemia cell line CCRF-CEM
Cancer Genet. Cytogenet.
cMYB is involved in the regulation of fetal hemoglobin production in adults
Blood
Differential sensitivity of v-Myb and c-Myb to Wnt-1-induced protein degradation
J. Biol. Chem.
Fbxw7 acts as an E3 ubiquitin ligase that targets c-Myb for nemo-like kinase (NLK)-induced degradation
J. Biol. Chem.
Double minute chromosomes containing MYB gene and NUP214-ABL1 fusion gene in T-cell leukemia detected by single nucleotide polymorphism DNA microarray and fluorescence in situ hybridization
Leuk. Res.
Nucleotide sequence of the retroviral leukemia gene v-myb and its cellular progenitor c-myb: the architecture of a transduced oncogene
Cell
The product of the retroviral transforming gene v-myb is a truncated version of the protein encoded by the cellular oncogene c-myb
Cell
Positive and negative regulation of c-Myb by cyclin D1, cyclin-dependent kinases, and p27 Kip1
Blood
Pim-1 kinase and p100 cooperate to enhance c-Myb activity
Mol. Cell
MicroRNA-mediated control of cell fate in megakaryocyte-erythrocyte progenitors
Dev. Cell
Mammalian cyclin-dependent kinases
Trends Biochem. Sci.
Characterization of the hemopoietic target cells for the avian leukemia virus E26
Virology
A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis
Cell
C-Myb, Menin, GATA-3, and MLL form a dynamic transcription complex that plays a pivotal role in human T helper type 2 cell development
Blood
Negative autoregulation of c-Myb activity by homodimer formation through the leucine zipper
J. Biol. Chem.
Oncogenic activation of c-Myb correlates with a loss of negative regulation by TIF1beta and ski
J. Biol. Chem.
Solution structure of a specific DNA complex of the Myb DNA-binding domain with cooperative recognition helices
Cell
Aberrant expression of an amplified c-myb oncogene in two cell lines from a colon carcinoma
Proc. Natl. Acad. Sci. U. S. A.
c-Myb is essential for early T cell development
Genes Dev.
FLASH acts as a co-activator of the transcription factor c-Myb and localizes to active RNA polymerase II foci
Oncogene
MYB transcription factor genes as regulators for plant responses: an overview
Physiol. Mol. Biol. Plants
Modulation of c-Myb-induced transcription activation by a phosphorylation site near the negative regulatory domain
Proc. Natl. Acad. Sci. U. S. A.
p89c-Myb is not required for fetal or adult hematopoiesis
Genesis
In vivo expression of an aberrant MYB-GATA1 fusion induces leukemia in the presence of GATA1 reduced levels
Leukemia
Critical functions for c-Myb at three checkpoints during thymocyte development
Nat. Immunol.
c-Myb binding sites in haematopoietic chromatin landscapes
PLoS One
The highly conserved DNA-binding domains of A-, B- and c-Myb differ with respect to DNA-binding, phosphorylation and redox properties
Nucleic Acids Res.
c-Myb supports erythropoiesis through the transactivation of KLF1 and LMO2 expression
Blood
Oncogenic activation of c-Myb by carboxyl-terminal truncation leads to decreased proteolysis by the ubiquitin-26S proteasome pathway
Oncogene
Alteration of proteolytic processing of c-Myb as a consequence of its truncation in murine myeloid leukemia
Leukemia
Identification of the leukemogenic protein of avian myeloblastosis virus and of its normal cellular homologue
Proc. Natl. Acad. Sci. U. S. A.
Recurrent fusions in MYB and MYBL1 define a common, transcription factor-driven oncogenic pathway in salivary gland adenoid cystic carcinoma
Cancer Discov.
Optimized approach for ion proton RNA sequencing reveals details of RNA splicing and editing features of the transcriptome
PLoS One
Variant-aware saturating mutagenesis using multiple Cas9 nucleases identifies regulatory elements at trait-associated loci
Nat. Genet.
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.
The BioGRID interaction database: 2017 update
Nucleic Acids Res.
Intestinal adenoma formation and MYC activation are regulated by cooperation between MYB and Wnt signaling
Cell Death Differ.
In vitro differentiation of c-myb(−/−) ES cells reveals that the colony forming capacity of unilineage macrophage precursors and myeloid progenitor commitment are c-Myb independent
Oncogene
Mechanism of c-myc regulation by c-Myb in different cell lineages
Mol. Cell. Biol.
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