Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: CBFB
Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38): 16:67,029,149-67,101,058 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q22.1 | Cleidocranial dysplasia 2 | 620099 | Autosomal dominant | 3 |
The CBFB gene encodes the beta subunit of the core-binding factor protein. The alpha subunit is encoded by 3 different genes: CBFA1 (RUNX2; 600211), CBFA2 (RUNX1; 151385), and CBFA3 (RUNX3; 600210). The complex acts as a transcription factor. RUNX alpha subunits bind to DNA via a Runt domain, whereas the beta subunit increases the affinity of the alpha subunit for DNA but shows no DNA binding by itself (review by Cohen, 2009).
Liu et al. (1993) cloned the human CBFB gene. The gene was identified as part of a fusion gene with MYH11 (160745) in leukemic cells derived from patients with acute myeloid leukemia type M4Eo (see AML, 601626), which is commonly associated with a pericentric inversion of chromosome 16, inv(16)(p13q22). The MYH11 gene maps to 16p13 and the CBFB gene maps to 16q22. The cDNA clones identified by Liu et al. (1993) showed strong homology to the murine DNA-binding factor CBF-beta gene identified by Wang et al. (1993).
Ogawa et al. (1993) also cloned the mouse Pebp2b gene and cDNAs representing 3 different splice variants.
The CBFB gene maps to chromosome 16q22 (Liu et al., 1993).
The acquired immunodeficiency syndrome (AIDS) virus, HIV-1, produces Vif, which counteracts host antiviral defense by highjacking a ubiquitin ligase complex consisting of CUL5 (601741), ELOC (TCEB1; 600788), ELOB (TCEB2; 600787), and RBX1 (603814) that targets the restriction factor APOBEC3G (607113) for degradation. Using affinity tag/purification mass spectrometry, Jager et al. (2012) showed that Vif also recruited CBFB to this ubiquitin ligase complex. CBFB allowed the reconstitution of a recombinant 6-protein assembly that elicited specific polyubiquitination activity with APOBEC3G, but not with APOBEC3A (607109). RNA knockdown and genetic complementation studies demonstrated that CBFB was required for Vif-mediated degradation of APOBEC3G and the preservation of HIV-1 infectivity. Vif from the simian immunodeficiency virus also bound to and required Cbfb to degrade rhesus Apobec3g, indicating functional conservation across primate species. Jager et al. (2012) proposed that disruption of the CBFB-Vif interaction might restrict HIV-1 and be a supplemental antiviral therapy.
Independently, Zhang et al. (2012) identified the role of CBFB in Vif-mediated degradation of APOBEC3G. The N-terminal region of Vif was required for interaction with CBFB, and Vif interacted with regions of CBFB distinct from those used by CBFB to interact with RUNX. Zhang et al. (2012) suggested that the CBFB-Vif interaction is a potential target for intervention against HIV-1.
CBFB-MYH11 Fusion Gene
Leukemic cells derived from patients with acute myeloid leukemia type M4Eo (see AML, 601626) often carry a pericentric inversion of chromosome 16, inv(16)(p13q22). Liu et al. (1993) determined the breakpoints of this inversion and found that it created a CBFB/MYH11 fusion gene. Analysis of 6 different leukemic cell lines with this inversion showed that CBFB breakpoints were the same in all cell lines, located close to the 3-prime end of the coding region with only the last 17 amino acids deleted. This breakpoint is also located at a sequence used for alternative splicing. There were 3 different breakpoints in the MYH11 gene. All of the rearrangements maintained the reading frame of the fusion transcript. Core-binding factor (CBF) binds to the core site of murine leukemia virus and also to the enhancers of the T-cell receptor genes, and the core site appears to be a major genetic determinant of the tissue specificity of leukemias induced by the murine leukemia virus. One of the CBF alpha subunits, RUNX1, is found to be disrupted in the characteristic t(8;21) translocation in the M2 subtype of acute myeloid leukemia. Liu et al. (1993) suggested that elucidation of the genes involved as fusion partners in an inversion leading to a common form of adult leukemia should allow the development of a mouse model and a sensitive RT-PCR test for specific diagnosis and assessment of residual disease after treatment.
Liu et al. (1995) provided a review of leukemia pathogenesis related to CBFB. They suggested that it will be interesting to see whether variant fusions between CBFB and another gene exist as a result of translocation between 16q and another chromosome. The study of such variants might shed light on the mechanism of genesis by the inversion 16 fusion gene. Whether the abnormal eosinophils in the circulation in patients with inv(16) are part of the malignant cell population or a result of a secondary response could not be determined. Although the distribution of breakpoints in the introns of the 2 participating genes was heterogeneous, a surprisingly high incidence of breaks was observed in a small (370 bp) intron of the MYH11 gene. CBFB and AML1 encode the 2 subunits of the transcription factor CBF, and alterations of either one are associated with acute myeloid leukemia.
To examine the effects of the inv(16)(p13;q22) on myelopoiesis, Kogan et al. (1998) generated transgenic mice expressing the chimeric fusion protein in myeloid cells. Neutrophil maturation was impaired. Although the transgenic mice had normal numbers of circulating neutrophils, their bone marrow contained increased numbers of immature neutrophilic cells, which exhibited abnormal characteristics. In addition, the fusion protein inhibited neutrophilic differentiation in colonies derived from hematopoietic progenitors. Coexpression of both the fusion protein and activated NRAS (164790) induced a more severe phenotype characterized by abnormal nuclear morphology indicative of granulocytic dysplasia. These results showed that the fusion protein impairs neutrophil development and provided evidence that alterations in Pebp2 can contribute to the genesis of myelodysplasia.
The inv(16) fuses most of CBFB to the C terminus of MYH11. CBFB is a transcription factor that does not bind DNA directly but interacts with the AML1 DNA-binding transcription factor (RUNX1; 151385) on chromosome 21q to increase its ability to bind DNA and regulate transcription. AML1 is one of the most frequently mutated genes in human leukemia. It is disrupted by the t(8;21), t(3;21), and t(16;21) in acute myeloid leukemia and by the t(12;21) in childhood B-cell acute lymphocytic leukemia (ALL). By disrupting CBFB, the inv(16) also disrupts AML1 functions. Together, these chromosomal rearrangements account for nearly one-quarter of all AML cases and one-fifth of all childhood B-cell ALL-containing discernible chromosomal abnormalities. Lutterbach et al. (1999) showed that the inv(16) fusion protein cooperates with the largest form of AML1, termed AML-1B, to repress transcription. This cooperativity requires the ability of the translocation fusion protein to bind to AML-1B. Mutation analysis and cell fractionation experiments indicated that the inv(16) fusion protein acts in the nucleus and that repression occurs when the complex is bound to DNA. They demonstrated that the C-terminal portion of the inv(16) fusion protein contains a repression domain, suggesting a molecular mechanism for AML1-mediated repression.
O'Reilly et al. (2000) reported a 43-year-old woman with acute myeloid leukemia type M4 and an abnormal karyotype, 46,XX,ins(16)(q22p13.1p13.3), resulting in a transcriptionally active CBFB/MYH11 fusion gene. O'Reilly et al. (2000) noted that the usual cause of the CBFB/MYH11 fusion gene is either inv(16)(p13;q22) or t(16;16)(p13;q22), both of which are predominantly associated with AML M4 cases with eosinophilia (M4Eo); however, the patient described by O'Reilly et al. (2000) lacked eosinophilia.
The transcription factor fusion CBFB-SMMHC, expressed in AML with the chromosome inversion inv(16)(p13q22), outcompetes wildtype CBFB for binding to the transcription factor RUNX1, deregulates RUNX1 activity in hematopoiesis, and induces AML. Treatment of inv(16) AML with nonselective cytotoxic chemotherapy results in a good initial response but limited long-term survival. Illendula et al. (2015) reported the development of a protein-protein interaction inhibitor, AI-10-49, that selectively binds to CBFB-SMMHC and disrupts its binding to RUNX1. AI-10-49 restores RUNX1 transcriptional activity, displays favorable pharmacokinetics, and delays leukemia progression in mice. Treatment of primary inv(16) AML patient blasts with AI-10-49 triggers selective cell death. Illendula et al. (2015) concluded that direct inhibition of the oncogenic CBFB-SMMHC fusion protein may be an effective therapeutic approach for inv(16) AML.
Cleidocranial Dysplasia 2
In 8 patients from 5 unrelated families with cleidocranial dysplasia (CLCD2; 620099), who were negative for mutation in the RUNX2 gene (600211), Beyltjens et al. (2023) identified heterozygosity for mutations in the CBFB gene (121360.0001-121360.0005). The mutations segregated with disease in the families for which DNA was available, and none of the mutations were found in public variant databases.
Somatic Mutations in Breast Cancer
To correlate the variable clinical features of estrogen-receptor-positive breast cancer (see 114480) with somatic alterations, Ellis et al. (2012) studied pretreatment tumor biopsies accrued from patients in 2 studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including 5 genes (RUNX1; CBFB; MYH9, 160775; MLL3, 606833; and SF3B1, 605590) previously linked to hematopoietic disorders.
Banerji et al. (2012) reported the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA (171834), TP53 (191170), AKT1 (164730), GATA3 (131320), and MAP3K1 (600982), Banerji et al. (2012) discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1.
CBF-beta forms a heterodimer with RUNX1. Both RUNX1 and CBF-beta are essential for hematopoiesis. Haploinsufficiency of RUNX2 (also called CBFA1; 600211), causes cleidocranial dysplasia (119600) and is essential in skeletal development by regulating osteoblast differentiation and chondrocyte maturation. Mice deficient in Cbfb (Cbfb -/-) die at midgestation. To investigate the function of Cbfb in skeletal development, Yoshida et al. (2002) rescued hematopoiesis of Cbfb -/- mice introducing Cbfb using the Gata1 promoter. The rescued Cbfb-null mice recapitulated fetal liver hematopoiesis in erythroid and megakaryocytic lineages and survived until birth, but showed severely delayed bone formation Although mesenchymal cells differentiated into immature osteoblasts, intramembranous bones were poorly formed. Yoshida et al. (2002) demonstrated that Cbf-beta was necessary for the efficient DNA binding of Runx2 and for Runx2-dependent transcriptional activation.
Using a 'knock-in' strategy, Kundu et al. (2002) generated mouse embryonic stem (ES) cells that expressed Cbfb fused in-frame to a cDNA encoding green fluorescent protein (GFP). Mice heterozygous for the fusion had normal life spans and appeared normal, but Cbfb(GFP/GFP) pups died within the first day after birth. These mice exhibited a delay in endochondral and intramembranous ossification as well as in chondrocyte differentiation, similar to but less severe than delays observed in Runx2 -/- mice. Thus, Kundu et al. (2002) demonstrated that Cbf-beta is expressed in developing bone and forms a functional interaction with Runx2, and that Cbfb(GFP) is a hypomorphic allele. The fusion allele maintains sufficient function in hematopoietic cells to bypass the early embryonic lethality. Kundu et al. (2002) raised the possibility that mutations in CBFB may be responsible for some cases of cleidocranial dysplasia that are not linked to mutations in RUNX2.
Miller et al. (2002) rescued fetal liver hematopoiesis in Cbf-beta-deficient embryos by introducing a transgene encoding a green fluorescent protein fusion protein (GFP/Cbf-beta) expressed from the promoter and enhancer of the Tek gene (600221). Tek is a vascular endothelial-specific receptor tyrosine kinase that is essential for the formation and remodeling of the vascular network. The gene is expressed in all endothelial cells throughout development and in the adult, and in a fraction of hematopoietic stem cells and committed hematopoietic progenitors in the fetal liver and adult bone marrow. The rescued mice died at birth with severe defects in skeletal development, although intramembranous ossification occurred to some extent. Although fetal liver hematopoiesis was restored at embryonic day 12.5, by embryonic day 17.5 significant impairments in lymphopoiesis and myelopoiesis were observed. Thus, Miller et al. (2002) concluded that the Cbf-beta subunit is required for hematopoietic stem cell emergence, bone formation, and normal differentiation of lymphoid and myeloid lineage cells.
In a 4-year-old boy (patient 1) with cleidocranial dysplasia (CLCD2; 620099), Beyltjens et al. (2023) identified heterozygosity for a de novo splice site variant (c.78+1G-T, NM_022845.3) in intron 1 of the CBFB gene. The variant was not found in the dbSNP, ExAC, or gnomAD databases. Analysis of cDNA from the patient and his mother demonstrated that the variant creates an alternative splice donor site, causing deletion of the last 5 nucleotides of exon 1 resulting in a frameshift and a premature stop codon (Cys25TyrfsTer2). The patient exhibited bilateral 'clavicula bipartita' as well as maxillary hypoplasia, shortening of distal phalanges, and pseudoepiphyses at the second and fifth metacarpals.
In a 7-year-old boy (patient 2) with cleidocranial dysplasia (CLCD2; 620099), Beyltjens et al. (2023) identified heterozygosity for a de novo deletion (c.283-1039_400-7568del, NM_022845.5) encompassing exon 4 of the CBFB gene. The variant was not present in the dbSNP, ExAC, or gnomAD databases. RNA-seq analysis of patient blood confirmed the presence of the heterozygous in-frame deletion. The patient had left-sided 'clavicula bipartita' and right-sided clavicular hypoplasia, as well as delayed eruption of deciduous teeth, shortening of the distal phalanges, pseudoepiphyses at the second metacarpals, and delayed carpal ossification. He also exhibited mild developmental delay.
In a woman and her mother (patients 3 and 4) with cleidocranial dysplasia (CLCD2; 620099), Beyltjens et al. (2023) identified heterozygosity for a 2-bp duplication (c.295_296dup, NM_022845.3) in exon 4 of the CBFB gene, causing a frameshift predicted to result in a premature termination codon (Pro100LeufsTer3). The duplication was not found in the dbSNP, ExAC, or gnomAD databases. The daughter had right-sided 'clavicula bipartita' and 4 supernumerary teeth; her mother had aplasia of the clavicles and broad thumbs.
In a 5-year-old girl and her mother (patients 5 and 6) with cleidocranial dysplasia (CLCD2; 620099), Beyltjens et al. (2023) identified heterozygosity for a c.247C-T transition (c.247C-T, NM_022845.3) in exon 3 of the CBFB gene, resulting in an arg83-to-ter (R83X) substitution. The variant was not found in the dbSNP, ExAC, or gnomAD databases. The proband had a large anterior fontanel, bilateral 'clavicula bipartita,' and hypodontia as well as bilateral sensorineural hearing loss and mild developmental delay. Her mother, who had normal clavicles, had 13 supernumerary teeth and bilateral hearing loss.
In a 5-year-old girl and her mother (patients 7 and 8) with cleidocranial dysplasia (CLCD2; 620099), Beyltjens et al. (2023) identified heterozygosity for a splice site mutation (c.283-2A-G, NM_022845.3) in intron 3 of the CBFB gene. The variant was not found in the dbSNP, ExAC, or gnomAD databases; RNA samples were not available for functional analysis. The proband had a large anterior fontanel, prominent forehead, left-sided 'clavicula bipartita' and bent right clavicle, hypoplastic distal phalanges of the fingers and toes, and pseudoepiphyses of the metacarpals and metatarsals, as well as delayed ossification and generalized osteopenia. She had moderate developmental delay and presented at age 3 years with failure to thrive, recurrent hypercalcemia, hypercalciuria, bilateral nephrocalcinosis, and reduced parathyroid hormone level; by age 5, she had stage 4 chronic kidney disease. Her mother did not recall any skeletal concerns but did report dental anomalies at age 8 that resulted in removal of all teeth; her adult dentition was normal.
Banerji, S., Cibulskis, K., Rangel-Escareno, C., Brown, K. K., Carter, S. L., Frederick, A. M., Lawrence, M. S., Sivachenko, A. Y., Sougnez, C., Zou, L., Cortes, M. L., Fernandez-Lopez, J. C., and 35 others. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486: 405-409, 2012. [PubMed: 22722202] [Full Text: https://doi.org/10.1038/nature11154]
Beyltjens, T., Boudin, E., Revencu, N., Boeckx, N., Bertrand, M., Schutz, L., Haack, T. B., Weber, A., Biliouri, E., Vinksel, M., Zagozen, A., Peterlin, B., and 9 others. Heterozygous pathogenic variants involving CBFB cause a new skeletal disorder resembling cleidocranial dysplasia. J. Med. Genet. 60: 498-504, 2023. [PubMed: 36241386] [Full Text: https://doi.org/10.1136/jmg-2022-108739]
Cohen, M. M., Jr. Perspectives on RUNX genes: an update. Am. J. Med. Genet. 149A: 2629-2646, 2009. [PubMed: 19830829] [Full Text: https://doi.org/10.1002/ajmg.a.33021]
Ellis, M. J., Ding, L., Shen, D., Luo, J., Suman, V. J., Wallis, J. W., Van Tine, B. A., Hoog, J., Goiffon, R. J., Goldstein, T. C., Ng, S., Lin, L., and 47 others. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 486: 353-360, 2012. [PubMed: 22722193] [Full Text: https://doi.org/10.1038/nature11143]
Illendula, A., Pulikkan, J. A., Zong, H., Grembecka, J., Xue, L., Sen, S., Zhou, Y., Boulton, A., Kuntimaddi, A., Gao, Y., Rajewski, R. A., Guzman, M. L., Castilla, L. H., Bushweller, J. H. A small-molecule inhibitor of the aberrant transcription factor CBF-beta-SMMHC delays leukemia in mice. Science 347: 779-784, 2015. [PubMed: 25678665] [Full Text: https://doi.org/10.1126/science.aaa0314]
Jager, S., Kim, D. Y., Hultquist, J. F., Shindo, K., LaRue, R. S., Kwon, E., Li, M., Anderson, B. D., Yen, L., Stanley, D., Mahon, C., Kane, J., Franks-Skiba, K., Cimermancic, P., Burlingame, A., Sali, A., Craik, C. S., Harris, R. S., Gross, J. D., Krogan, N. J. Vif hijacks CBF-beta to degrade APOBEC3G and promote HIV-1 infection. Nature 481: 371-375, 2012. [PubMed: 22190037] [Full Text: https://doi.org/10.1038/nature10693]
Kogan, S. C., Lagasse, E., Atwater, S., Bae, S., Weissman, I., Ito, Y., Bishop, J. M. The PEBP2-beta-MYH11 fusion created by inv(16)(p13;q22) in myeloid leukemia impairs neutrophil maturation and contributes to granulocytic dysplasia. Proc. Nat. Acad. Sci. 95: 11863-11868, 1998. [PubMed: 9751756] [Full Text: https://doi.org/10.1073/pnas.95.20.11863]
Kundu, M., Javed, A., Jeon, J.-P., Horner, A., Shum, L., Eckhaus, M., Muenke, M., Lian, J. B., Yang, Y., Nuckolls, G. H., Stein, G. S., Liu, P. P. Cbf-beta interacts with Runx2 and has a critical role in bone development. Nature Genet. 32: 639-644, 2002. [PubMed: 12434156] [Full Text: https://doi.org/10.1038/ng1050]
Liu, P. P., Hajra, A., Wijmenga, C., Collins, F. S. Molecular pathogenesis of the chromosome 16 inversion in the M4Eo subtype of acute myeloid leukemia. Blood 85: 2289-2302, 1995. Note: Erratum: Blood 89: 1842 only, 1997. [PubMed: 7727763]
Liu, P., Tarle, S. A., Hajra, A., Claxton, D. F., Marlton, P., Freedman, M., Siciliano, M. J., Collins, F. S. Fusion between transcription factor CBF-beta/PEBP2-beta and a myosin heavy chain in acute myeloid leukemia. Science 261: 1041-1044, 1993. [PubMed: 8351518] [Full Text: https://doi.org/10.1126/science.8351518]
Lutterbach, B., Hou, Y., Durst, K. L., Hiebert, S. W. The inv(16) encodes an acute myeloid leukemia 1 transcriptional corepressor. Proc. Nat. Acad. Sci. 96: 12822-12827, 1999. [PubMed: 10536006] [Full Text: https://doi.org/10.1073/pnas.96.22.12822]
Miller, J., Horner, A., Stacy, T., Lowrey, C., Lian, J. B., Stein, G., Nuckolls, G. H., Speck, N. A. The core-binding factor beta subunit is required for bone formation and hematopoietic maturation. Nature Genet. 32: 645-649, 2002. [PubMed: 12434155] [Full Text: https://doi.org/10.1038/ng1049]
O'Reilly, J., Chipper, L., Springall, F., Herrmann, R. A unique structural abnormality of chromosome 16 resulting in a CBF-beta-MYH11 fusion transcript in a patient with acute myeloid leukemia, FAB M4. Cancer Genet. Cytogenet. 121: 52-55, 2000. [PubMed: 10958941] [Full Text: https://doi.org/10.1016/s0165-4608(00)00235-1]
Ogawa, E., Inuzuka, M., Maruyama, M., Satake, M., Naito-Fujimoto, M., Ito, Y., Shigesada, K. Molecular cloning and characterization of PEBP2-beta, the heterodimeric partner of a novel Drosophila runt-related DNA binding protein PEBP2-alpha. Virology 194: 314-331, 1993. [PubMed: 8386878] [Full Text: https://doi.org/10.1006/viro.1993.1262]
Wang, S., Wang, Q., Crute, B. E., Melnikova, I. N., Keller, S. R., Speck, N. A. Cloning and characterization of subunits of the T-cell receptor and murine leukemia virus enhancer core-binding factor. Molec. Cell. Biol. 13: 3324-3339, 1993. [PubMed: 8497254] [Full Text: https://doi.org/10.1128/mcb.13.6.3324-3339.1993]
Yoshida, C. A., Furuichi, T., Fujita, T., Fukuyama, R., Kanatani, N., Kobayashi, S., Satake, M., Takada, K., Komori, T. Core-binding factor beta interacts with Runx2 and is required for skeletal development. Nature Genet. 32: 633-638, 2002. [PubMed: 12434152] [Full Text: https://doi.org/10.1038/ng1015]
Zhang, W., Du, J., Evans, S. L., Yu, Y., Yu, X.-F. T-cell differentiation factor CBF-beta regulates HIV-1 Vif-mediated evasion of host restriction. Nature 481: 376-379, 2012. [PubMed: 22190036] [Full Text: https://doi.org/10.1038/nature10718]