Elsevier

Gene

Volume 665, 30 July 2018, Pages 6-17
Gene

Gene wiki review
MYB – A regulatory factor in hematopoiesis

https://doi.org/10.1016/j.gene.2018.04.065Get rights and content

Abstract

MYB is a transcription factor which was identified in birds as a viral oncogene (v-MYB). Its cellular counterpart was subsequently isolated as c-MYB which has three functional domains - DNA binding domain, transactivation domain and negative regulatory domain. c-MYB is essential for survival, and deletion of both alleles of the gene results in embryonic death. It is highly expressed in hematopoietic cells, thymus and neural tissue, and required for T and B lymphocyte development and erythroid maturation. Additionally, aberrant MYB expression has been found in numerous solid cancer cells and human leukemia. Recent studies have also implicated c-MYB in the regulation of expression of fetal hemoglobin which is highly beneficial to the β-hemoglobinopathies (beta thalassemia and sickle cell disease). These findings suggest that MYB could be a potential therapeutic target in leukemia, and possibly also a target for therapeutic increase of fetal hemoglobin in the β-hemoglobinopathies.

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.

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