Alternative titles; symbols
HGNC Approved Gene Symbol: MYB
Cytogenetic location: 6q23.3 Genomic coordinates (GRCh38): 6:135,181,308-135,219,172 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q23.3 | {T-cell acute lymphoblastic leukemia} | 3 |
The avian myeloblastosis virus causes myeloid leukemia in chickens. Expression of RNA sequences homologous to AMV was detected by Westin et al. (1982) in all immature myeloid and lymphoid T cells and in the single erythroid cell line examined, but not in mature T cells or in B cells, including lymphoblast cell lines from patients with Burkitt lymphoma. No solid tumors showed c-amv mRNA.
MIR150 (611114) is a microRNA (miRNA) specifically expressed in mature lymphocytes, but not their progenitors. Using loss- and gain-of-function gene targeting approaches for Mir150 with conditional and partial ablation of Myb in mice, Xiao et al. (2007) showed that Mir150 controlled Myb expression in vivo in a dose-dependent manner over a narrow range of miRNA and Myb concentrations, dramatically affecting lymphocyte development and the humoral immune response. They concluded that MYB is a critical target of MIR150.
Using yeast 2-hybrid and coimmunoprecipitation analyses, Saether et al. (2007) found that Mi2-alpha (CHD3; 602120) interacted with human MYB. MYB and Mi2-alpha had 2 interaction surfaces: one linking the MYB DNA-binding domain to the N-terminal region of Mi2-alpha, and the other linking the C-terminal region of Mi2-alpha with the FAETL region of MYB. Functional analysis following coexpression of Mi2-alpha and MYB in CV-1 cells revealed that Mi2-alpha had both a helicase-dependent repressive function and helicase-independent activating function, and that MYB exploited the activating function of Mi2-alpha. Knockdown of Mi2-alpha in MYB-expressing human erythroleukemia K562 cells demonstrated that Mi2-alpha could coactivate transcription of endogenous MYB target genes. Mi2-alpha coactivation was exerted primarily on nonsumoylated MYB. Mi2-alpha was also able to enhance MYB-p300 (EP300; 602700) transactivational activity.
In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements called superenhancers, which recruit much of the cell's transcriptional apparatus and are defined by extensive acetylation of histone H3 lysine-27 (H3K27ac). In a subset of T-ALL (see 613065) cases, Mansour et al. (2014) found that heterozygous somatic mutations are acquired that introduce binding motifs for the MYB transcription factor in a precise noncoding site, which creates a superenhancer 7.5 kb upstream of the TAL1 (187040) oncogene. Among 146 unselected pediatric primary T-ALL samples collected at diagnosis, 8 patients (5.5%) had heterozygous indels 2 to 18 bp in length that overlapped at the same clearly defined hotspot. Indels at this site were referred to as 'mutation of the TAL1 enhancer,' or MuTE. MYB binds to the new site introduced by MuTE and recruits its H3K27 acetylase-binding partner CBP (600140), as well as core components of a major leukemogenic transcriptional complex that contains RUNX1 (151385), GATA3 (131320), and TAL1 itself. Additionally, most endogenous superenhancers found in T-ALL cells are occupied by MYB and CBP, which suggests a general role for MYB in superenhancer initiation. Mansour et al. (2014) estimated that MuTE abnormalities account for about half of the cases with unexplained monoallelic overexpression of TAL1. Mansour et al. (2014) concluded that this study identified a genetic mechanism responsible for the generation of oncogenic superenhancers in malignant cells.
Using Hlf (142385) reporter mice and Myb -/- mice, Yokomizo et al. (2019) found that Myb was not required for formation of hematopoietic clusters or erythromyeloid progenitors (EMPs) from hemogenic endothelium. Instead, Myb appeared to be involved in maintenance or expansion of EMPs.
By study of somatic cell hybrids, Dalla-Favera et al. (1982) assigned the onc gene for avian myeloblastosis virus to chromosome 6. Harper et al. (1983) assigned the MYB locus to chromosome 6q22-6q24 by in situ hybridization. This is the point of break in translocations involved in T-cell acute lymphatic leukemia and in some ovarian cancers and melanomas. McBride et al. (1983) assigned MYB to 6q15-q21. By in situ hybridization, Janssen et al. (1986) localized MYB to 6q21-q23. Together with earlier localizations, this gives an SRO of 6q22-q23.
Using a single interspecific backcross for linkage mapping, Justice et al. (1990) demonstrated the location of the Myb gene in relation to other genes on mouse chromosome 10. Using RFLVs (restriction fragment length variations) in multipoint backcrosses, Shimizu et al. (1992) also mapped the Myb gene in relation to other loci on mouse chromosome 10.
Harper et al. (1983) referred to increase in c-MYB in a tumor cell line with a translocation between 6q and chromosome 7.
In 4 of 5 cases of malignant melanoma, Trent et al. (1983) found chromosome alterations, including deletion and translocation in the long arm of chromosome 6, specifically in the 6q15-6q23 region. They pointed out that the MYB oncogene maps to this region. Becher et al. (1983), reviewing cytologic findings in malignant melanoma in their own and reported cases, likewise pointed to a high incidence of structural aberration of 6q (segment q11-q31), whereas the short arm remains structurally unchanged, though its genetic material is often duplicated, as in the case of isochromosome-6p in one of their cases. They pointed out that these findings accentuate the interest in the relationships found between specific HLA haplotypes and familial malignant melanoma (Hawkins et al., 1981; Pellegris et al., 1982). Tumor-specific antigens have been found in malignant melanoma.
Yokota et al. (1986) concluded that alterations are found in oncogenes MYC, HRAS, or MYB in more than one-third of human solid tumors. Amplification of MYC was found in advanced widespread tumors and in aggressive primary tumors. Apparent allelic deletions of HRAS and MYB could be correlated with progression and metastasis of carcinomas and sarcomas.
Barletta et al. (1987) found that deletions of the long arm of chromosome 6 (6q-), frequently found in hematopoietic neoplasms including acute lymphoblastic leukemias, non-Hodgkin lymphomas, and (less frequently) myeloid leukemias, are accompanied by high levels of MYB mRNA levels despite the fact that in situ hybridization studies in 6 such malignancies showed that the MYB locus was not allelic. It was found to be retained on band 6q22, which is consistently bordered by the chromosomal breakpoints in both interstitial and terminal 6q- deletions.
Linnenbach et al. (1988) found an alteration in the MYB gene in a cell line derived from a primary melanoma in the vertical growth phase (VGP). The alteration at the molecular level correlated with a 6q22 chromosomal abnormality. (Melanoma begins with radial growth without competence from metastasis and later progresses to the vertical growth phase, which is associated with metastasis.)
Meese et al. (1989) extended the physical map surrounding the MYB locus and provided further evidence of rearrangement of chromosome 6 in malignant melanoma.
Lahortiga et al. (2007) identified a duplication of the MYB oncogene in 8.4% of individuals with T cell acute lymphoblastic leukemia (T-ALL) and in 5 T-ALL cell lines. The duplication was associated with a 3-fold increase in MYB expression, and knockdown of MYB expression initiated T cell differentiation. The results identified duplication of MYB as an oncogenic event and suggested that MYB could be a therapeutic target in human T-ALL. The duplication of MYB was detected by array comparative genomic hybridization (array CGH).
Since the MYB gene encodes proteins that are critical for hematopoietic cell proliferation and development, Ratajczak et al. (1992) hypothesized that disrupting MYB function might be an effective therapeutic strategy for controlling leukemic cell growth. They developed a model for testing the in vivo efficacy of antisense oligodeoxynucleotides for disrupting MYB. Their model was a human leukemia-scid mouse chimera with K562 cells derived from a patient with chronic myelogenous leukemia (151410). The cells carried the Philadelphia chromosome and the BCR-ABL hybrid gene which could be used to track the human cells in the mouse host. The MYB antisense oligodeoxynucleotides were phosphorothioate-modified. Animals treated with the antisense MYB survived at least 3.5 times longer than control animals. In addition, animals receiving antisense MYB DNA had significantly less disease at the 2 sites most frequently involved by leukemic cell infiltration, the CNS and the ovary.
Mice null for the thrombopoietin receptor Mpl (159530) are profoundly thrombocytopenic, as are humans with mutations in the MPL gene. To identify mutations capable of ameliorating thrombocytopenia and to define the molecular pathways regulating platelet production, Carpinelli et al. (2004) performed a suppressor screen in Mpl-null mice using N-ethyl-N-nitrosourea (ENU) mutagenesis. They showed that mutations in the Myb gene caused a myeloproliferative syndrome and supraphysiologic expansion of megakaryocyte and platelet production in the absence of thrombopoietin signaling.
Sandberg et al. (2005) created mice with a homozygous met303-to-val (M303V) mutation in the Myb gene, which disrupted the interaction between Myb and the transcriptional coactivator p300. The biologic consequences of the mutation included thrombocytosis, megakaryocytosis, anemia, lymphopenia, and absence of eosinophils. Detailed analysis of hematopoiesis in mutant mice revealed distinct blocks in T-cell, B-cell, and red blood cell development, as well as a 10-fold increase in the number of hematopoietic stem cells. Cell cycle analysis showed that twice as many hematopoietic stem cells were actively cycling in mutant mice compared with wildtype mice. Sandberg et al. (2005) concluded that MYB, through its interaction with p300, controls the proliferation and differentiation of hematopoietic stem and progenitor cells.
Barletta, C., Pelicci, P.-G., Kenyon, L. C., Smith, S. D., Dalla-Favera, R. Relationship between the c-myb locus and the 6q- chromosomal aberration in leukemias and lymphomas. Science 235: 1064-1067, 1987. [PubMed: 3469751] [Full Text: https://doi.org/10.1126/science.3469751]
Becher, R., Gibas, Z., Sandberg, A. A. Chromosome 6 in malignant melanoma. Cancer Genet. Cytogenet. 9: 173-175, 1983. [PubMed: 6850556] [Full Text: https://doi.org/10.1016/0165-4608(83)90038-9]
Carpinelli, M. R., Hilton, D. J., Metcalf, D., Antonchuk, J. L., Hyland, C. D., Mifsud, S. L., Di Rago, L., Hilton, A. A., Willson, T. A., Roberts, A. W., Ramsay, R. G., Nicola, N. A., Alexander, W. S. Suppressor screen in Mpl -/- mice: c-Myb mutation causes supraphysiological production of platelets in the absence of thrombopoietin signaling. Proc. Nat. Acad. Sci. 101: 6553-6558, 2004. [PubMed: 15071178] [Full Text: https://doi.org/10.1073/pnas.0401496101]
Dalla-Favera, R., Franchini, G., Martinotti, S., Wong-Staal, F., Gallo, R. C., Croce, C. M. Chromosomal assignment of the human homologues of feline sarcoma virus and avian myeloblastosis virus onc genes. Proc. Nat. Acad. Sci. 79: 4714-4717, 1982. [PubMed: 6289315] [Full Text: https://doi.org/10.1073/pnas.79.15.4714]
Franchini, G., Wong-Staal, F., Baluda, M. A., Lengel, C., Tronick, S. R. Structural organization and expression of human DNA sequences related to the transforming gene of avian myeloblastosis virus. Proc. Nat. Acad. Sci. 80: 7385-7389, 1983. [PubMed: 6324165] [Full Text: https://doi.org/10.1073/pnas.80.24.7385]
Harper, M. E., Franchini, G., Love, J., Simon, M. I., Gallo, R. C., Wong-Staal, F. Chromosomal sublocalization of human c-myb and c-fes cellular onc genes. Nature 304: 169-171, 1983. [PubMed: 6866112] [Full Text: https://doi.org/10.1038/304169a0]
Hawkins, B. R., Dawkins, R. L., Hockey, A., Houliston, J. B., Kirk, R. L. Evidence for linkage between HLA and malignant melanoma. Tissue Antigens 17: 540-541, 1981. [PubMed: 6950540] [Full Text: https://doi.org/10.1111/j.1399-0039.1981.tb00742.x]
Janssen, J. W. G., Vernole, P., de Boer, P. A. J., Oosterhuis, J. W., Collard, J. G. Sublocalization of c-myb to 6q21-q23 by in situ hybridization and c-myb expression in a human teratocarcinoma with 6q rearrangements. Cytogenet. Cell Genet. 41: 129-135, 1986. [PubMed: 3007038] [Full Text: https://doi.org/10.1159/000132217]
Justice, M. J., Siracusa, L. D., Gilbert, D. J., Heisterkamp, N., Groffen, J., Chada, K., Silan, C. M., Copeland, N. G., Jenkins, N. A. A genetic linkage map of mouse chromosome 10: localization of eighteen molecular markers using a single interspecific backcross. Genetics 125: 855-866, 1990. [PubMed: 1975791] [Full Text: https://doi.org/10.1093/genetics/125.4.855]
Lahortiga, I., De Keersmaecker, K., Van Vlierberghe, P., Graux, C., Cauwelier, B., Lambert, F., Mentens, N., Beverloo, H. B., Pieters, R., Speleman, F., Odero, M. D., Bauters, M., Froyen, G., Marynen, P., Vandenberghe, P., Wlodarska, I., Meijerink, J. P. P., Cools, J. Duplication of the MYB oncogene in T cell acute lymphoblastic leukemia. Nature Genet. 39: 593-595, 2007. [PubMed: 17435759] [Full Text: https://doi.org/10.1038/ng2025]
Linnenbach, A. J., Huebner, K., Reddy, E. P., Herlyn, M., Parmiter, A. H., Nowell, P. C., Koprowski, H. Structural alteration in the MYB protooncogene and deletion within the gene encoding alpha-type protein kinase C in human melanoma cell lines. Proc. Nat. Acad. Sci. 85: 74-78, 1988. [PubMed: 2829178] [Full Text: https://doi.org/10.1073/pnas.85.1.74]
Majello, B., Kenyon, L. C., Dalla-Favera, R. Human c-myb protooncogene: nucleotide sequence of cDNA and organization of the genomic locus. Proc. Nat. Acad. Sci. 83: 9636-9640, 1986. [PubMed: 3540945] [Full Text: https://doi.org/10.1073/pnas.83.24.9636]
Mansour, M. R., Abraham, B. J., Anders, L., Berezovskaya, A., Gutierrez, A., Durbin, A. D., Etchin, J., Lawton, L., Sallan, S. E., Silverman, L. B., Loh, M. L., Hunger, S. P., Sanda, T., Young, R. A., Look, A. T. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346: 1373-1377, 2014. [PubMed: 25394790] [Full Text: https://doi.org/10.1126/science.1259037]
McBride, O. W., Swan, D. C., Tronick, S. R., Gol, R., Klimanis, D., Moore, D. E., Aaronson, S. A. Regional chromosomal localization of N-ras, K-ras-1, K-ras-2 and myb oncogenes in human cells. Nucleic Acids Res. 11: 8221-8236, 1983. [PubMed: 6672765] [Full Text: https://doi.org/10.1093/nar/11.23.8221]
Meese, E., Meltzer, P. S., Witkowski, C. M., Trent, J. M. Molecular mapping of the oncogene MYB and rearrangements in malignant melanoma. Genes Chromosomes Cancer 1: 88-94, 1989. [PubMed: 2487149] [Full Text: https://doi.org/10.1002/gcc.2870010114]
Pelicci, P.-G., Lanfrancone, L., Brathwaite, M. D., Wolman, S. R., Dalla-Favera, R. Amplification of the c-myb oncogene in a case of human acute myelogenous leukemia. Science 224: 1117-1121, 1984. [PubMed: 6585957] [Full Text: https://doi.org/10.1126/science.6585957]
Pellegris, G., Illeni, M. T., Rovini, D., Vaglini, M., Cascinelli, N., Ghidoni, A. HLA complex and familial malignant melanoma. Int. J. Cancer 29: 621-623, 1982. [PubMed: 6955289] [Full Text: https://doi.org/10.1002/ijc.2910290604]
Ratajczak, M. Z., Kant, J. A., Luger, S. M., Hijiya, N., Zhang, J., Zon, G., Gewirtz, A. M. In vivo treatment of human leukemia in a scid mouse model with c-myb antisense oligodeoxynucleotides. Proc. Nat. Acad. Sci. 89: 11823-11827, 1992. [PubMed: 1281545] [Full Text: https://doi.org/10.1073/pnas.89.24.11823]
Rushlow, K. E., Lautenberger, J. A., Papas, T. S., Baluda, M. A., Perbal, B., Chirikjian, J. G., Reddy, E. P. Nucleotide sequence of the transforming gene of avian myeloblastosis virus. Science 216: 1421-1423, 1982. [PubMed: 6283631] [Full Text: https://doi.org/10.1126/science.6283631]
Saether, T., Berge, T., Ledsaak, M., Matre, V., Alm-Kristansen, A. H., Dahle, O., Aubry, F., Gabrielsen, O. S. The chromatin remodeling factor Mi-2-alpha acts as a novel co-activator for human c-Myb. J. Biol. Chem. 282: 13994-14005, 2007. [PubMed: 17344210] [Full Text: https://doi.org/10.1074/jbc.M700755200]
Sandberg, M. L., Sutton, S. E., Pletcher, M. T., Wiltshire, T., Tarantino, L. M., Hogenesch, J. B., Cooke, M. P. c-Myb and p300 regulate hematopoietic stem cell proliferation and differentiation. Dev. Cell 8: 153-166, 2005. [PubMed: 15691758] [Full Text: https://doi.org/10.1016/j.devcel.2004.12.015]
Shimizu, A., Sakai, Y., Ohno, K., Masaki, S., Kuwano, R., Takahashi, Y., Miyashita, N., Watanabe, T. A molecular genetic linkage map of mouse chromosome 10, including the Myb, S100b, Pah, Sl, and Ifg genes. Biochem. Genet. 30: 529-535, 1992. [PubMed: 1359872] [Full Text: https://doi.org/10.1007/BF01037591]
Trent, J. M., Rosenfeld, S. B., Meyskens, F. L. Chromosome 6q involvement in human malignant melanoma. Cancer Genet. Cytogenet. 9: 177-180, 1983. [PubMed: 6850557] [Full Text: https://doi.org/10.1016/0165-4608(83)90039-0]
Westin, E. H., Gallo, R. C., Arya, S. K., Eva, A., Souza, L. M., Baluda, M. A., Aaronson, S. A., Wong-Staal, F. Differential expression of the amv gene in human hematopoietic cells. Proc. Nat. Acad. Sci. 79: 2194-2198, 1982. [PubMed: 6954533] [Full Text: https://doi.org/10.1073/pnas.79.7.2194]
Xiao, C., Calado, D. P., Galler, G., Thai, T.-H., Patterson, H. C., Wang, J., Rajewsky, N., Bender, T. P., Rajewsky, K. MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell 131: 146-159, 2007. Note: Erratum: Cell 165: 1027 only, 2016. [PubMed: 17923094] [Full Text: https://doi.org/10.1016/j.cell.2007.07.021]
Yokomizo, T., Watanabe, N., Umemoto, T., Matsuo, J., Harai, R., Kihara, Y., Nakamura, E., Tada, N., Sato, T., Takaku, T., Shimono, A., Takizawa, H., Nakagata, N., Mori, S., Kurokawa, M., Tenen, D. G., Osato, M., Suda, T., Komatsu, N. Hlf marks the developmental pathway for hematopoietic stem cells but not for erythro-myeloid progenitors. J. Exp. Med. 216: 1599-1614, 2019. [PubMed: 31076455] [Full Text: https://doi.org/10.1084/jem.20181399]
Yokota, J., Tsunetsugu-Yokota, Y., Battifora, H., Le Fevre, C., Cline, M. J. Alterations of myc, myb, and ras(Ha) proto-oncogenes in cancers are frequent and show clinical correlation. Science 231: 261-265, 1986. [PubMed: 3941898] [Full Text: https://doi.org/10.1126/science.3941898]