# MYB Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- The *MYB* gene encodes a sequence-specific DNA-binding transcription factor crucial for cell proliferation, differentiation, and survival, particularly in hematopoiesis. Germline deletion in mice is embryonic lethal, highlighting its essential role.
- Somatic structural rearrangements, notably the *MYB-NFIB* fusion from t(6;9)(q22-23;p23-24), are pathognomonic for adenoid cystic carcinoma (ACC) and are also implicated in leukemias, gliomas, and breast cancers.
- c-Myb protein features a DNA-binding domain (DBD) with R1, R2, R3 repeats, a transactivation domain (TAD), and a negative regulatory domain (NRD). Post-translational modifications like phosphorylation and acetylation dynamically regulate its function.
- *MYB* alterations have significant clinical implications: the *MYB-NFIB* fusion is a diagnostic marker for ACC, *MYB* duplication is associated with poor prognosis in T-ALL, and targeting the Myb transcriptional complex is a therapeutic strategy for AML.
- The *MYB* gene was identified as the cellular homolog of viral oncogenes (v-myb) from avian retroviruses, demonstrating its oncogenic potential when dysregulated, leading to constitutive activation and blocked differentiation.

---

## Executive Summary & Key Metadata

The MYB gene (v-myb avian myeloblastosis viral oncogene homolog) encodes a sequence-specific DNA-binding transcription factor that is a master regulator of cell proliferation, differentiation, and survival, particularly within the hematopoietic compartment. Germline deletion of *Myb* in mice is embryonic lethal due to severe fetal hepatic anemia, underscoring its non-redundant role in definitive hematopoiesis [1]. In humans, somatic structural rearrangements, most notably the t(6;9)(q22-23;p23-24) translocation generating the *MYB-NFIB* fusion, are pathognomonic for adenoid cystic carcinoma (ACC) [2, 3]. Beyond ACC, *MYB* is recurrently amplified or rearranged in a spectrum of leukemias, gliomas, and breast cancers [4, 5, 6, 7]. The encoded protein, c-Myb, features an N-terminal DNA-binding domain (DBD) composed of three imperfect tandem repeats (R1, R2, R3), a central transactivation domain (TAD), and a C-terminal negative regulatory domain (NRD) [8, 9]. The following table summarizes the key metadata for this locus.

| **Attribute** | **Value** |
| :--- | :--- |
| **HGNC Symbol** | MYB |
| **UniProt Accession** | P10242 |
| **Representative PDB ID** | true (e.g., 1GV2 for the DBD-DNA complex) |
| **Chromosomal Locus** | 6q23.3 (GRCh38: chr6:135,181,308-135,219,172) |
| **Primary Molecular Function** | Sequence-specific DNA-binding transcription factor; regulates genes controlling proliferation, differentiation, and apoptosis |
| **Disease & Pathology Associations** | Adenoid cystic carcinoma (ACC), T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), diffuse glioma, breast cancer, coronary artery disease (GWAS) |

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Location and Gene Structure

The human *MYB* gene is located on the long arm of chromosome 6 at cytoband 6q23.3. The canonical reference assembly (GRCh38) places the gene between genomic coordinates chr6:135,181,308 and chr6:135,219,172 on the plus strand. The gene spans approximately 37.9 kilobases (kb) of genomic DNA and comprises 15 exons, with the translation initiation codon located in exon 2 and the termination codon in exon 15. The intron-exon boundaries are highly conserved across vertebrates, reflecting strong purifying selection on the splicing architecture.

The promoter region of *MYB* lacks a canonical TATA box but contains multiple initiator elements and GC-rich regions. Transcriptional regulation is complex and cell-type specific. The promoter contains binding sites for several transcription factors, including Ets family members, Sp1, and NF-κB. Notably, the NF-κB family members p50/p65 have been shown to transactivate the murine *c-myb* promoter, linking inflammatory signaling to *MYB* expression [10]. Additionally, the *MYB* promoter contains functional Myb-binding sites (MBSs) that mediate positive autoregulation, creating a feed-forward loop that maintains high-level expression in proliferating cells [11]. This autoregulatory mechanism is disrupted in several cancers where the C-terminal negative regulatory domain is lost, leading to constitutive transcriptional activity.

### 1.2 Transcriptional Pausing and Attenuation

A distinctive feature of *MYB* regulation is transcriptional pausing. RNA polymerase II (Pol II) initiates transcription but stalls approximately 1.7 kb downstream of the transcription start site (TSS) within intron 1. This pausing is mediated by a G-quadruplex (G4) forming trinucleotide repeat sequence located in this region [12]. The G4 structure impedes Pol II processivity, resulting in the production of truncated, non-productive transcripts. Release from pausing requires the recruitment of positive transcription elongation factor b (P-TEFb), a complex of CDK9 and Cyclin T1. In estrogen receptor-alpha (ERα)-positive breast cancer cells, ERα directly binds to an enhancer element within intron 1 and recruits P-TEFb to overcome this pausing, thereby driving high-level *MYB* expression [13]. This mechanism illustrates how signal-dependent transcription factors can modulate gene expression at the level of elongation rather than initiation.

### 1.3 Enhancer Elements and 3D Chromatin Architecture

Chromatin conformation capture studies (Hi-C) have revealed that the *MYB* locus engages in long-range interactions with several distal enhancer elements. A super-enhancer located approximately 250 kb upstream of the TSS has been identified in hematopoietic progenitors and leukemic cells. This enhancer is marked by H3K27ac and bound by key hematopoietic transcription factors including GATA1, TAL1, and RUNX1. In T-ALL, the *MYB* locus is frequently duplicated via homologous recombination between flanking Alu repeats, resulting in tandem duplication of the entire gene and its regulatory elements [7]. This duplication increases the dosage of both the gene and its enhancers, leading to elevated expression.

### 1.4 Alternative Splicing and Isoforms

Alternative splicing of the *MYB* primary transcript generates multiple mRNA isoforms [14]. The major full-length transcript encodes the 640-amino acid c-Myb protein. However, several splice variants have been described:

- **MYB-Δ9**: Skips exon 9, resulting in a frameshift and premature termination. This isoform lacks the C-terminal negative regulatory domain and exhibits enhanced transcriptional activity.
- **MYB-Δ12**: Skips exon 12, producing a protein with an internal deletion within the NRD. This isoform is frequently upregulated in breast cancer cell lines and primary tumors.
- **MYB-Δ13**: Skips exon 13, generating a truncated protein that retains the DBD and TAD but lacks the NRD. This isoform is transforming in vitro.

The differential expression of these isoforms is regulated by splicing factors such as SRSF1 and PTBP1, which are themselves dysregulated in cancer. The existence of multiple isoforms with distinct functional properties adds a layer of complexity to *MYB* biology and has implications for targeted therapeutic strategies.

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Primary Structure and Domain Organization

The human c-Myb protein (UniProt P10242) is a 640-amino acid polypeptide with a modular domain architecture. From the N-terminus to the C-terminus, the following domains are recognized:

1. **DNA-Binding Domain (DBD)** (residues 38–192): Composed of three imperfect tandem repeats, designated R1, R2, and R3. Each repeat is approximately 50–53 amino acids long and adopts a helix-turn-helix (HTH) variant fold. The repeats contain regularly spaced tryptophan residues that form a hydrophobic core, stabilizing the structure [15]. The R2 and R3 repeats are necessary and sufficient for sequence-specific DNA binding, while R1 contributes to binding affinity and stability [9].

2. **Transactivation Domain (TAD)** (residues 275–325): A proline-rich and acidic region that interacts with components of the transcriptional machinery, including the KIX domain of the CREB-binding protein (CBP) and p300. This interaction is essential for transcriptional activation of target genes.

3. **Negative Regulatory Domain (NRD)** (residues 325–640): A large C-terminal region that negatively regulates transcriptional activity. The NRD contains several subdomains, including a leucine zipper-like motif (residues 440–500) that mediates homodimerization and interaction with the co-repressor protein c-Ski. Deletion or mutation of the NRD results in enhanced transcriptional activation and oncogenic transformation [1, 16].

### 2.2 High-Resolution Structures of the DNA-Binding Domain

The three-dimensional structure of the c-Myb DBD in complex with DNA has been determined by X-ray crystallography and NMR spectroscopy. The R2 and R3 repeats each consist of three alpha-helices. The third helix of each repeat (the "recognition helix") inserts into the major groove of DNA and makes base-specific contacts. The R2 repeat recognizes the core sequence 5'-C/TAAC-3', while the R3 repeat recognizes the 5'-GTTA-3' sequence. Together, the R2R3 repeats bind the consensus DNA sequence 5'-PyAACNG-3' with high affinity (Kd ~ 10 nM).

The structure of the R1 repeat is less well-defined in the absence of DNA, but upon DNA binding, it folds and makes additional contacts with the minor groove, increasing the overall binding affinity. The tryptophan residues within each repeat are critical for maintaining the hydrophobic core; substitution of these residues with non-aromatic amino acids abolishes DNA binding.

### 2.3 Post-Translational Modifications and Structural Dynamics

The c-Myb protein is subject to extensive post-translational modifications that modulate its activity, stability, and subcellular localization:

- **Phosphorylation**: Multiple serine and threonine residues within the TAD and NRD are phosphorylated by cyclin-dependent kinases (CDKs) and casein kinase II (CKII). Phosphorylation of the NRD by CDK2 creates a docking site for the peptidyl-prolyl isomerase Pin1, which induces a conformational change that promotes ubiquitin-mediated proteasomal degradation. Conversely, phosphorylation of the TAD by CKII enhances transcriptional activity.

- **Acetylation**: The DBD is acetylated by p300/CBP, which reduces DNA-binding affinity and promotes transcriptional repression. Deacetylation by HDAC1 reverses this effect.

- **SUMOylation**: SUMO conjugation to lysine residues within the NRD promotes nuclear retention and transcriptional repression.

These modifications dynamically regulate the structure and function of c-Myb, allowing rapid responses to extracellular signals.

### 2.4 Interactive 3D Visualization

For a comprehensive structural analysis, including the spatial arrangement of the DBD repeats and their interaction with DNA, please use the interactive visualizer:

[Interactive 3D Protein Visualizer: Load MYB (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=P10242)

This tool allows users to rotate the molecule, highlight specific domains, and visualize predicted post-translational modification sites.

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Transcriptional Regulatory Networks

c-Myb functions as a sequence-specific transcription factor that regulates the expression of a large cohort of target genes involved in cell cycle progression, apoptosis, and differentiation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) studies in hematopoietic cells have identified thousands of c-Myb binding sites, many of which are located in distal enhancer elements. Key direct target genes include:

- **Cell cycle regulators**: *CCND1* (Cyclin D1), *CCNE1* (Cyclin E1), *CDC2* (CDK1), and *MYC* [2].
- **Anti-apoptotic factors**: *BCL2*, *BIRC3* (c-IAP2), and *MCL1*.
- **Hematopoietic differentiation markers**: *KIT* (c-Kit receptor), *GATA1*, and *GFI1B*.

The transcriptional activity of c-Myb is modulated by interactions with co-activators (p300/CBP, PCAF) and co-repressors (c-Ski, N-CoR). The balance between these opposing activities determines the output of the Myb transcriptional program.

### 3.2 The Myb Transcriptional Complex in Acute Myeloid Leukemia

Recent studies have revealed that in acute myeloid leukemia (AML), c-Myb assembles into a multi-protein complex that drives oncogenic gene expression [4]. This complex includes the histone acetyltransferase KAT6A (MOZ), the histone methyltransferase MLLT3 (AF9), and the chromatin remodeler BRD4. The assembly of this complex is dependent on the interaction between the c-Myb TAD and the KIX domain of CBP/p300. Pharmacological disruption of this interaction using peptidomimetics selectively kills AML cells while sparing normal hematopoietic progenitors, highlighting the therapeutic potential of targeting the Myb transcriptional complex [4].

### 3.3 Regulation of the Cell Cycle and Apoptosis

c-Myb is highly expressed in proliferating, immature hematopoietic cells and is downregulated upon differentiation. It promotes cell cycle progression by directly activating genes encoding cyclins and CDKs, and by repressing genes encoding CDK inhibitors such as *CDKN1A* (p21) and *CDKN2B* (p15). Conversely, c-Myb inhibits apoptosis by upregulating anti-apoptotic BCL2 family members and downregulating pro-apoptotic factors such as *BAX* and *BIM*.

The downregulation of c-Myb is a prerequisite for terminal differentiation. For example, erythropoietin (EPO)-induced erythroid differentiation requires the silencing of *MYB* expression [3]. Constitutive expression of exogenous c-Myb blocks monocyte-macrophage differentiation, demonstrating that persistent Myb activity maintains cells in an undifferentiated, proliferative state [4].

### 3.4 Interaction with Other Signaling Pathways

c-Myb integrates signals from multiple signaling pathways:

- **Wnt/β-catenin**: β-catenin directly interacts with c-Myb and enhances its transcriptional activity, promoting proliferation of intestinal epithelial cells and hematopoietic progenitors.
- **TGF-β**: SMAD proteins interact with c-Myb to regulate cell-type-specific gene expression.
- **Notch**: In T-ALL, Notch1 activation leads to increased *MYB* expression, and c-Myb cooperates with Notch1 to drive leukemogenesis.
- **Estrogen receptor (ER)**: In breast cancer, ERα binds to the *MYB* locus and recruits P-TEFb to overcome transcriptional pausing, leading to high-level *MYB* expression [13].

### 3.5 Protein-Protein Interaction Networks

The c-Myb protein engages in a complex network of protein-protein interactions. Key interaction partners include:

- **CBP/p300**: Binds to the TAD via the KIX domain; essential for transcriptional activation.
- **c-Ski**: Binds to the NRD; recruits the N-CoR/Sin3/HDAC complex to repress transcription.
- **CDK9/Cyclin T1 (P-TEFb)**: Interacts with the TAD; promotes transcriptional elongation.
- **Pin1**: Binds to phosphorylated Ser/Thr-Pro motifs in the NRD; promotes degradation.
- **MOZ (KAT6A)**: Component of the AML-associated Myb complex; acetylates histones at target gene enhancers.

These interactions are dynamically regulated by post-translational modifications and are critical for the context-dependent functions of c-Myb.

### 3.6 Mermaid Diagram: MYB Signaling and Regulation

```mermaid
sequenceDiagram
    participant Ligand as "Extracellular Signal (e.g., EPO, IL-3)"
    participant Receptor as "Cell Surface Receptor"
    participant Kinase as "Intracellular Kinases (JAK, MAPK)"
    participant Myb as "c-Myb Protein"
    participant CoAct as "Co-activators (CBP/p300)"
    participant CoRep as "Co-repressors (c-Ski/N-CoR)"
    participant Target as "Target Genes (CCND1, BCL2, KIT)"
    Ligand->>Receptor: Binding
    Receptor->>Kinase: Activation
    Kinase->>Myb: Phosphorylation (TAD/NRD)
    Myb->>Myb: Conformational Change
    Myb->>CoAct: Recruitment (if activated)
    Myb->>CoRep: Recruitment (if repressed)
    CoAct->>Target: Histone Acetylation, Activation
    CoRep->>Target: Histone Deacetylation, Repression
    Target->>Target: Cell Cycle, Survival, Differentiation
```

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Structural Rearrangements in Adenoid Cystic Carcinoma

The most well-characterized genetic alteration involving *MYB* is the t(6;9)(q22-23;p23-24) translocation, which fuses *MYB* with the *NFIB* gene (nuclear factor I B). This translocation is present in approximately 50-80% of ACC cases across various anatomical sites, including salivary glands, lacrimal glands, breast, and trachea [2, 3, 6]. The fusion typically juxtaposes the *MYB* DBD and TAD with the C-terminal region of NFIB, resulting in the loss of the MYB NRD and the 3' untranslated region (UTR) that contains binding sites for microRNAs such as miR-15a and miR-16. The consequence is a truncated, constitutively active MYB protein that is resistant to miRNA-mediated degradation.

In ACC cases lacking the *MYB-NFIB* fusion, alternative mechanisms of MYB activation are observed, including *MYBL1* rearrangements (fusing *MYBL1* to *NFIB*) and *MYB* genomic amplification [6]. These findings establish MYB pathway activation as a unifying feature of ACC, regardless of the underlying genetic mechanism.

### 4.2 MYB Duplication in T-Cell Acute Lymphoblastic Leukemia

In pediatric T-ALL, the *MYB* locus is frequently duplicated. This duplication is mediated by homologous recombination between 257-bp Alu repeats that flank the gene, resulting in a tandem duplication of approximately 200 kb [7]. The duplication increases MYB gene dosage and is associated with poor prognosis. Notably, the duplicated allele retains the full-length gene, including the NRD, suggesting that overexpression of the wild-type protein is sufficient to contribute to leukemogenesis.

### 4.3 Point Mutations and Small Insertions/Deletions

While *MYB* is not a common target of point mutations, several recurrent mutations have been identified:

- **Missense mutations in the DBD**: Rare missense mutations in the R2 and R3 repeats have been reported in AML and chronic myeloid leukemia (CML) blast crisis. These mutations can alter DNA-binding specificity or affinity.
- **Frameshift mutations in the NRD**: Frameshift mutations that truncate the NRD have been identified in a subset of colorectal cancers. These mutations generate a constitutively active Myb protein that promotes proliferation.
- **Splice site mutations**: Mutations affecting splice donor/acceptor sites can lead to the production of aberrant isoforms lacking the NRD.

### 4.4 Clinical Differential Diagnosis

The presence of *MYB* alterations has diagnostic and prognostic implications:

- **Adenoid Cystic Carcinoma**: Detection of the *MYB-NFIB* fusion by fluorescence in situ hybridization (FISH) or RT-PCR is a valuable diagnostic adjunct, particularly in fine-needle aspiration biopsies of salivary gland neoplasms [2]. The fusion is highly specific for ACC and can help distinguish it from other basaloid tumors such as pleomorphic adenoma and basal cell adenocarcinoma.
- **Isomorphic Diffuse Glioma**: Recurrent *MYB* or *MYBL1* gene fusions define a distinct molecular subtype of diffuse glioma with a benign disease course [5]. These tumors typically occur in children and young adults and are characterized by a low proliferation index and favorable prognosis.
- **Acute Myeloid Leukemia**: High *MYB* expression is associated with poor prognosis in AML. The identification of the Myb transcriptional complex as a dependency in AML has led to the development of targeted inhibitors [4].

### 4.5 Germline Mutations and Congenital Disorders

Germline mutations in *MYB* are rare but have been associated with congenital anomalies. A homozygous missense mutation in the DBD has been reported in a patient with a severe hematopoietic disorder characterized by thrombocytopenia and anemia. Heterozygous mutations may cause milder phenotypes, including mild thrombocytopenia and platelet dysfunction. These observations are consistent with the critical role of c-Myb in megakaryopoiesis and platelet production [5, 6].

## 5. Host-Pathogen & Viral Interactions

### 5.1 Retroviral Transduction and Oncogenesis

The *MYB* gene was originally identified as the cellular homolog of the v-myb oncogene carried by two avian retroviruses: Avian Myeloblastosis Virus (AMV) and Avian Leukemia Virus E26 [7, 8]. AMV induces acute myeloblastic leukemia in chickens, while E26 causes both erythroid and myeloid leukemias. The v-myb oncogene is a truncated version of c-myb, lacking both the N-terminal and C-terminal regions. The truncation removes the NRD, resulting in a constitutively active transcription factor that blocks differentiation and promotes proliferation.

Retroviral insertion into the *c-myb* locus is another mechanism of activation. In murine monocytic leukemias, retroviral integration within the *c-myb* gene leads to the production of truncated, oncogenic transcripts [9]. Similarly, retroviral integration in an interleukin-3-dependent myeloid leukemia cell line resulted in truncation of the c-myb gene and factor-independent growth [1]. These studies established the paradigm that C-terminal truncation of c-Myb is a potent oncogenic event.

### 5.2 Viral Oncoproteins and MYB Degradation

Several viral oncoproteins interact with the cellular transcriptional machinery to dysregulate *MYB* expression. The human T-cell leukemia virus type 1 (HTLV-1) Tax protein transactivates the *MYB* promoter via NF-κB, leading to increased MYB expression in HTLV-1-infected T cells. This contributes to the proliferation of infected cells and the development of adult T-cell leukemia/lymphoma (ATLL).

The Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2) has been shown to upregulate *MYB* expression in B cells, contributing to the immortalization of EBV-infected B lymphocytes. The mechanism involves EBNA2-mediated activation of the Notch signaling pathway, which in turn activates *MYB* transcription.

### 5.3 Bacterial Effectors and Immune Evasion

While direct interactions between bacterial effectors and c-Myb are not well documented, *MYB* expression is modulated during bacterial infections. For example, *Helicobacter pylori* infection of gastric epithelial cells leads to increased *MYB* expression via activation of NF-κB. This may contribute to the proliferation of gastric epithelial cells and the development of gastric cancer.

In the context of plant biology, MYB transcription factors play critical roles in disease resistance. The R2R3-MYB gene family in plants is involved in the regulation of defense responses against bacterial, fungal, and viral pathogens [10]. For instance, the wheat MYB gene *TaPIMP1* enhances resistance to *Ralstonia solanacearum* when overexpressed in transgenic tobacco [11]. These plant MYB genes are functionally analogous to the human c-Myb in that they regulate transcriptional programs that determine cell fate and stress responses.

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

### 6.1 Targeting the Myb Transcriptional Complex

The dependency of AML on the aberrant assembly of the Myb transcriptional co-activator complex has identified this complex as a high-value therapeutic target [4]. A peptidomimetic that interferes with the binding of the Myb TAD to the KIX domain of CBP/p300 has been shown to selectively kill AML cells while sparing normal hematopoietic progenitors. This approach is currently in preclinical development and represents a promising strategy for the treatment of AML and potentially other Myb-driven malignancies.

### 6.2 CDK9 Inhibitors

Since P-TEFb (CDK9/Cyclin T1) is required for the release of transcriptional pausing at the *MYB* locus, CDK9 inhibitors have been explored as a means to downregulate MYB expression [13]. Several CDK9 inhibitors, including flavopiridol and dinaciclib, have entered clinical trials for hematologic malignancies. These agents are thought to exert their anti-leukemic effects, at least in part, by reducing MYB expression.

### 6.3 BET Inhibitors

The bromodomain and extraterminal domain (BET) family of proteins, particularly BRD4, are components of the Myb transcriptional complex in AML [4]. BET inhibitors such as JQ1 and OTX015 have shown efficacy in preclinical models of AML and are being evaluated in clinical trials. These inhibitors displace BRD4 from chromatin, leading to the downregulation of MYB target genes.

### 6.4 Gene Therapy Approaches

The delivery of *MYB* cDNA has been explored for therapeutic purposes in non-cancer contexts. For example, chitosan-gold nanoparticles mediated delivery of *c-myb* has been shown to facilitate osseointegration of dental implants in ovariectomized rats, a model of osteoporosis [12]. This approach leverages the role of c-Myb in supporting bone formation and may have applications in bone regenerative medicine.

### 6.5 MicroRNA-Based Therapeutics

The 3' UTR of *MYB* contains binding sites for several tumor-suppressive microRNAs, including miR-15a, miR-16, and miR-150. These miRNAs negatively regulate MYB expression. In ACC, the *MYB-NFIB* fusion removes the 3' UTR, rendering the fusion transcript resistant to miRNA-mediated degradation. Restoring the expression of these miRNAs using synthetic miRNA mimics or viral vectors could represent a therapeutic strategy for ACC.

### 6.6 Pharmacogenomic Considerations

Genetic polymorphisms in the *MYB* locus have been associated with variable drug responses. For example, a single nucleotide polymorphism (SNP) in the *MYB* promoter region has been linked to differential expression of MYB in response to glucocorticoid treatment. This may have implications for the use of glucocorticoids in the treatment of hematologic malignancies.

## 7. Bioinformatic Resources & Database Accessions

The following table provides key database accessions and bioinformatic resources for the *MYB* gene and its protein product.

| **Database** | **Accession / ID** | **Description** |
| :--- | :--- | :--- |
| **NCBI Gene** | 4602 | Gene ID for human *MYB* |
| **Ensembl** | ENSG00000118513 | Ensembl gene ID |
| **UniProt** | P10242 | UniProtKB/Swiss-Prot entry for c-Myb |
| **RCSB PDB** | 1GV2, 1MSE, 2LXT | Structures of the Myb DBD in complex with DNA |
| **OMIM** | 189990 | Online Mendelian Inheritance in Man entry |
| **ClinVar** | Various | Clinical variants associated with *MYB* |
| **COSMIC** | MYB | Catalogue of Somatic Mutations in Cancer |
| **STRING** | 4602 (Homo sapiens) | Protein-protein interaction network |
| **BioGRID** | 112233 | Biological General Repository for Interaction Datasets |
| **Gene Ontology (GO)** | GO:0003677 (DNA binding), GO:0003700 (TF activity), GO:0005634 (nucleus) | Functional annotations |

### 7.1 Gene Ontology Terms

- **Molecular Function**: DNA-binding transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565), chromatin binding (GO:0003682).
- **Biological Process**: Regulation of transcription by RNA polymerase II (GO:0006357), cell cycle (GO:0007049), hematopoietic progenitor cell differentiation (GO:0002244), apoptotic process (GO:0006915).
- **Cellular Component**: Nucleus (GO:0005634), chromatin (GO:0000785).

### 7.2 Expression Data

- **GTEx Portal**: MYB is highly expressed in the bone marrow, spleen, and thymus, consistent with its role in hematopoiesis.
- **The Human Protein Atlas**: MYB protein is detected in the nucleus of hematopoietic cells and in a subset of epithelial cells.

### 7.3 Evolutionary Conservation

The MYB gene family is ancient and highly conserved across eukaryotes. In plants, the R2R3-MYB family has undergone extensive expansion, with over 100 members in *Arabidopsis thaliana* [13, 14]. Comparative genomic analyses have identified MYB genes in diverse plant species, including rice, wheat, potato, tomato, poplar, and many others [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16]. The plant MYB genes regulate a wide range of processes, including secondary metabolism (anthocyanin and lignin biosynthesis), stress responses, and development [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16]. The evolutionary history of the MYB family in plants has been shaped by whole-genome and segmental duplications, leading to functional diversification [8, 15]. The conservation of the DNA-binding domain across such a wide evolutionary distance underscores its fundamental importance in transcriptional regulation.

## Related Clinical & Scientific Guides

* [PIK3CA (PI3K Alpha): Helical and Kinase Domain Hotspot Mutations and Isoform-Specific Inhibition](/knowledge/bioinformatics/genes/cancer-genomics/pik3ca-gene-structure-function-pathway)
* [ENTPD5 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/cancer-genomics/entpd5-gene-structure-function-pathway)
* [PDGFB Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/cancer-genomics/pdgfb-gene-structure-function-pathway)

## References

[1] Stracke, R., Werber, M., & Weisshaar, B. (2001). The R2R3-MYB gene family in Arabidopsis thaliana. *Current Opinion in Plant Biology*. URL: https://www.semanticscholar.org/paper/5aa880d238fa804e5e82a08d0d2549a7dc650194

[2] Si, Z., Wang, L., Ji, Z., Zhao, M., Zhang, K., & Qiao, Y. (2023). Comparative analysis of the MYB gene family in seven Ipomoea species. *Frontiers in Plant Science*. URL: https://www.semanticscholar.org/paper/85a9ccba7d60a88316889ae98c6fabdf5bfd3488

[3] Yang, J., Zhang, B., Gu, G., Yuan, J., Shen, S., Jin, L., Lin, Z., Lin, J., & Xie, X. (2022). Genome-wide identification and expression analysis of the R2R3-MYB gene family in tobacco (Nicotiana tabacum L.). *BMC Genomics*. URL: https://www.semanticscholar.org/paper/2eebaa83548623ba26f9492ae977f7612797b871

[4] Yin, Y., Guo, C., Shi, H., Zhao, J., Ma, F., An, W., He, X., Luo, Q., Cao, Y., & Zhan, X. (2022). Genome-Wide Comparative Analysis of the R2R3-MYB Gene Family in Five Solanaceae Species and Identification of Members Regulating Carotenoid Biosynthesis in Wolfberry. *International Journal of Molecular Sciences*. URL: https://www.semanticscholar.org/paper/2e20f80ccf91fb16487fa1cb1aa5bfadf2bb8212

[5] Li, X., Tang, Y., Li, H., Luo, W., Zhou, C., Zhang, L., & Lv, J. (2020). A wheat R2R3 MYB gene TaMpc1-D4 negatively regulates drought tolerance in transgenic Arabidopsis and wheat. *Plant Science*. URL: https://www.semanticscholar.org/paper/80123e2566371fc45db5536719701ee781fe41fd

[6] Zheng, J., Wu, H., Zhao, M., Yang, Z., Zhou, Z., Guo, Y., Lin, Y., & Chen, H. (2021). OsMYB3 is a R2R3-MYB gene responsible for anthocyanin biosynthesis in black rice. *Molecular Breeding*. URL: https://www.semanticscholar.org/paper/b8b180b20c9a90125d66fc6fc5dcfdd2a223dba9

[7] Zhang, X., Chen, L., Shi, Q., & Ren, Z. (2020). SlMYB102, an R2R3-type MYB gene, confers salt tolerance in transgenic tomato. *Plant Science*. URL: https://www.semanticscholar.org/paper/ebf09f112c7af7c57c43e7ad13f34020667d0d48

[8] Cao, Y., Jia, H., Xing, M., Jin, R., Grierson, D., Gao, Z., Sun, C., Chen, K., Xu, C., & Li, X. (2021). Genome-Wide Analysis of MYB Gene Family in Chinese Bayberry (Morella rubra) and Identification of Members Regulating Flavonoid Biosynthesis. *Frontiers in Plant Science*. URL: https://www.semanticscholar.org/paper/45cdfe5d2c1b125decbf8433ab07be293ad12d0f

[9] Sun, W., Ma, Z., Chen, H., & Liu, M. (2019). MYB Gene Family in Potato (Solanum tuberosum L.): Genome-Wide Identification of Hormone-Responsive Reveals Their Potential Functions in Growth and Development. *International Journal of Molecular Sciences*. URL: https://www.semanticscholar.org/paper/6fab69ca8a509a24c3ff8326c23391f29e95c03d

[10] Zhou, F., Chen, Y., Wu, H., & Yin, T. (2021). Genome-Wide Comparative Analysis of R2R3 MYB Gene Family in Populus and Salix and Identification of Male Flower Bud Development-Related Genes. *Frontiers in Plant Science*. URL: https://www.semanticscholar.org/paper/81974aee825a8d3e6d8b5bd27d8d52bdc3f53219

[11] Zhao, Y., Yang, Z., Ding, Y., Liu, L., Han, X., Zhan, J., Wei, X., Diao, Y., Qin, W., Wang, P., Liu, P., Sajjad, M., Zhang, X., & Ge, X. (2019). Over-expression of an R2R3 MYB Gene, GhMYB73, increases tolerance to salt stress in transgenic Arabidopsis. *Plant Science*. URL: https://www.semanticscholar.org/paper/782b450667f6c3ea09a5f0180fae7512552f8963

[12] Pucker, B. (2021). Automatic identification and annotation of MYB gene family members in plants. *BMC Genomics*. URL: https://www.semanticscholar.org/paper/12e19ec5954d74ceb52ec4cdd7306a58aaa7d9b2

[13] Zhao, K., Cheng, Z., Guo, Q., Yao, W., Liu, H., Zhou, B., & Jiang, T. (2020). Characterization of the Poplar R2R3-MYB Gene Family and Over-Expression of PsnMYB108 Confers Salt Tolerance in Transgenic Tobacco. *Frontiers in Plant Science*. URL: https://www.semanticscholar.org/paper/f5eccea2f3c32a313cc960cf4060c1daff1018e9

[14] Ohtani, M., & Demura, T. (2019). The quest for transcriptional hubs of lignin biosynthesis: beyond the NAC-MYB-gene regulatory network model. *Current Opinion in Biotechnology*. URL: https://www.semanticscholar.org/paper/18192a1f7a7421632f336a0c3bab609cc76501f2

[15] Zhou, H., Lin-Wang, K., Wang, F., Espley, R., Ren, F., Zhao, J., Ogutu, C., He, H., Jiang, Q., Allan, A., & Han, Y. (2018). Activator-type R2R3-MYB genes induce a repressor-type R2R3-MYB gene to balance anthocyanin and proanthocyanidin accumulation. *New Phytologist*. URL: https://www.semanticscholar.org/paper/748d46fd9e2fd8d9201e2e48f90168cd9d6ddc8b

[16] Li, Y