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Other entities represented in this entry:
HGNC Approved Gene Symbol: MECOM
Cytogenetic location: 3q26.2 Genomic coordinates (GRCh38): 3:169,083,507-169,663,712 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q26.2 | Radioulnar synostosis with amegakaryocytic thrombocytopenia 2 | 616738 | Autosomal dominant | 3 |
The murine Evi1 gene encodes a protein that has multiple 28-amino acid repeats containing the consensus sequence found in the zinc finger domains of many transcriptional regulatory proteins. Activation of the expression of the Evi1 gene is frequently found in murine myeloid leukemias and leukemia cell lines and is due to retroviral insertions in the 5-prime region of the gene. To examine the role of the EVI1 gene in human leukemias, Morishita et al. (1990) cloned regions of the human locus corresponding to the coding region of the gene.
Using probes corresponding to coding regions of the gene, Morishita et al. (1990) demonstrated that the human EVI1 gene maps to chromosome 3q24-q28.
Gross (2018) mapped the MECOM gene to chromosome 3q26.2 based on an alignment of the MECOM sequence (GenBank BC143952) with the genomic sequence (GRCh38).
The EVI1 gene resides in a region that is translocated in acute nonlymphocytic leukemias with a t(3;5)(q25;q34) translocation. By in situ hybridization with metaphase chromosomes from a patient with a 3;5 translocation, Morishita et al. (1990) found that the EVI1 gene was translocated to the derivative chromosome 5. However, no rearrangements were detected by Southern blot analysis and no EVI1 transcripts were detected with RNA from leukemic blasts of 1 patient with the translocation. Since retroviral activation of Evi1 gene expression is one of the most common transforming events in murine myeloid leukemias, Morishita et al. (1992) evaluated the role of the EVI1 gene in human acute myelogenous leukemia in 116 patients. In 8 patients, the EVI1 gene was expressed and all but one patient had cytogenetically detectable translocations involving 3q26. To identify breakpoints, a restriction map that spanned 1,700 kb of the EVI1 locus was developed by pulsed field gel electrophoresis. In 2 patients rearrangements were found to be located 5-prime to the gene and, in 1 patient, 150 kb downstream from the 5-prime end of the gene. One of the 5-prime rearrangements, a case of t(3;3)(q21;q26), was shown to result in fusion of sequences from 3q21-q22 with the EVI1 locus.
Overexpression of the EVI1 gene appears to be a consistent feature of the 3q21q26 syndrome, an association of myeloid leukemia/myelodysplastic syndrome with a specific chromosomal aberration involving both 3q21 and 3q26, such as t(3;3)(q21;q26) or inv(3)(q21q26). The rearrangement in 3q26 occurs near the EVI1 locus, implicating it as the critical gene deregulated in the 3q21q26 syndrome. Ogawa et al. (1996) presented a structural abnormality of the EVI1 protein in a case of the 3q21q26 syndrome associated with the typical chromosome 3 inversion. The 3q26 breakpoint was located within an intron of the EVI1 gene, and resulted in overexpression of an aberrant form of EVI1 protein (normally unexpressed), in which the C-terminal 44 amino acids of the wildtype protein were truncated and replaced by 5 amino acids. The truncated EVI1 protein was shown to increase AP1 (165160) activity when expressed in NIH3T3 cells as its wildtype counterpart. The results of Ogawa et al. (1996) strongly supported the conclusion that the primary target for the 3q21q26 syndrome is the EVI1 gene which, in the chromosomal aberrations, is juxtaposed to a 3q21 locus containing a putative enhancer element.
Pekarsky et al. (1997) found that GR6 (LINC01565; 618259) was highly expressed in the UCSD-AML1 leukemia cell line, which contains a 3q21 breakpoint 1 kb 3-prime to the GR6 gene. GR6 also showed high expression in a leukemia patient cell line with a t(3;3)(q21;q26) translocation 5-prime to the GR6 gene. In the UCSD-AML1 leukemia cell line, Pekarsky et al. (1997) identified several intergenic fusion transcripts between GR6 and EVI1, including a fusion of GR6 exon 1 with EVI1 exon 2 and 2 different fusions of GR6 exon 4 with EVI1 exon 2, including 1 with a sequence from chromosome 3q26 that is not part of EVI1. The authors also identified an intergenic fusion transcript between RBPH1 (RPN1; 180470) and EVI1, with exon 1 of RBPH1 fused in-frame with exon 2 of EVI1.
In 3 unrelated Japanese children with radioulnar synostosis and amegakaryocytic thrombocytopenia-2 (RUSAT2; 616738), Niihori et al. (2015) identified heterozygous missense mutations in the MECOM gene (165215.0001-165215.0003) that were not found in unaffected relatives, 382 ethnically matched controls, or public variant databases.
Buonamici et al. (2004) generated a mouse model of EVI1-positive myelodysplasia by infecting mouse bone marrow cells with an EVI1-expressing retrovirus and transplanting them into lethally irradiated syngeneic recipients. EVI1 induced a fatal disease characterized by severe pancytopenia which did not progress to acute myeloid leukemia. The immediate effects of EVI1 were hyperproliferation of bone marrow cells and downregulation of the genes encoding the receptors for erythropoietin (EPOR; 133171) and thrombopoietin (MPL; 159530). These defects were not fatal, and the mice survived for approximately 10 months with compensated hematopoiesis before succumbing to fatal peripheral cytopenia.
Nucifora and Rowley (1995) reviewed the involvement of the AML1 gene (151385) in the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia. Three loci closely situated to each other on 3q26 are involved in fusions with AML1 in the 3;21 translocations: EVI1, EAP (RPL22; 180474), and MDS1 (600049). They pointed out that the order of the genes on 3q26 is TEL--EAP--MDS1--EVI1 and provided a diagram (their Figure 5) of the 3q26 region containing the EAP, MDS1, and EVI1 genes and of the various chimeric junctions they had isolated from t(3;21) patients. The functional EAP gene resides on chromosome 1p36; a pseudogene maps to 3q26.
In a 3-year-old Japanese girl (TRS1) with radioulnar synostosis and amegakaryocytic thrombocytopenia-2 (RUSAT2; 616738), Niihori et al. (2015) identified heterozygosity for a c.2266A-G transition (c.2266A-G, NM_001105078) in the MECOM gene, resulting in a thr756-to-ala (T756A) substitution at a highly conserved residue within the eighth zinc finger motif in the C-terminal zinc finger domain. The mutation was not present in her unaffected parents or healthy brother, in 382 ethnically matched controls, or in the dbSNP, 1000 Genomes Project, Human Genetic Variation, or ExAC databases. Luciferase assays using pAP1 (165160)-luc in transfected NIH3T3 and HEK293 cells demonstrated enhanced suppression of relative luciferase activity with the T756A mutant compared to wildtype EVI1, whereas luciferase assays using a p3TP-lux vector showed an attenuated response with the mutant. Niihori et al. (2015) suggested that the T756A mutant might represent a gain-of-function effect for AP1 and partial loss of function for TGF-beta (190180) signaling.
In an 8.75-year-old Japanese girl (TRS2) with radioulnar synostosis and amegakaryocytic thrombocytopenia-2 (RUSAT2; 616738), originally described by Sugita et al. (2007), Niihori et al. (2015) identified heterozygosity for a c.2252A-G transition (c.2252A-G, NM_001105078) in the MECOM gene, resulting in a his751-to-arg (H751R) substitution at a highly conserved residue within the eighth zinc finger motif in the C-terminal zinc finger domain. The mutation was not present in her unaffected parents, in 382 ethnically matched controls, or in the dbSNP, 1000 Genomes Project, Human Genetic Variation, or ExAC databases. Chromatin immunoprecipitation-qPCR assays showed a significant reduction in immunoprecipitated DNA with the H751R mutant compared to wildtype EVI1. Luciferase assays using pAP1 (165160)-luc in transfected NIH3T3 and HEK293 cells demonstrated enhanced suppression of relative luciferase activity with the H751R mutant compared to wildtype EVI1, whereas luciferase assays using a p3TP-lux vector showed an attenuated response with the mutant. Niihori et al. (2015) suggested that the H751R mutant might represent a gain-of-function effect for AP1 and partial loss of function for TGF-beta (190180) signaling.
In an 8-year-old Japanese boy (TRS3) with radioulnar synostosis and amegakaryocytic thrombocytopenia-2 (RUSAT2; 616738), originally reported by Yoshida et al. (2010), Niihori et al. (2015) identified heterozygosity for a c.2248C-T transition (c.2248C-T, NM_001105078) in the MECOM gene, resulting in an arg750-to-trp (R750W) substitution at a highly conserved residue within the eighth zinc finger motif in the C-terminal zinc finger domain. The mutation was not present in his unaffected mother, in 382 ethnically matched controls, or in the dbSNP, 1000 Genomes Project, Human Genetic Variation, or ExAC databases. DNA from the father was not available. Chromatin immunoprecipitation-qPCR assays showed a significant reduction in immunoprecipitated DNA with the R750W mutant compared to wildtype EVI1. Luciferase assays using pAP1 (165160)-luc in transfected NIH3T3 and HEK293 cells demonstrated enhanced suppression of relative luciferase activity with the R750W mutant compared to wildtype EVI1, whereas luciferase assays using a p3TP-lux vector showed an attenuated response with the mutant. Niihori et al. (2015) suggested that the R750W mutant might represent a gain-of-function effect for AP1 and partial loss of function for TGF-beta (190180) signaling.
Buonamici, S., Li, D., Chi, Y., Zhao, R., Wang, X., Brace, L., Ni, H., Saunthararajah, Y., Nucifora, G. EVI1 induces myelodysplastic syndrome in mice. J. Clin. Invest. 114: 713-719, 2004. Note: Erratum: J. Clin. Invest. 115: 2296 only, 2005. [PubMed: 15343390] [Full Text: https://doi.org/10.1172/JCI21716]
Gross, M. B. Personal Communication. Baltimore, Md. 3/16/2018.
Morishita, K., Parganas, E., Bartholomew, C., Sacchi, N., Valentine, M. B., Raimondi, S. C., Le Beau, M. M., Ihle, J. N. The human Evi-1 gene is located on chromosome 3q24-q28 but is not rearranged in three cases of acute nonlymphocytic leukemias containing t(3;5)(q25;q34) translocations. Oncogene Res. 5: 221-231, 1990. [PubMed: 2108405]
Morishita, K., Parganas, E., Willman, C. L., Whittaker, M. H., Drabkin, H., Oval, J., Taetle, R., Valentine, M. B., Ihle, J. N. Activation of EVI1 gene expression in human acute myelogenous leukemias by translocations spanning 300-400 kilobases on chromosome band 3q26. Proc. Nat. Acad. Sci. 89: 3937-3941, 1992. [PubMed: 1570317] [Full Text: https://doi.org/10.1073/pnas.89.9.3937]
Niihori, T., Ouchi-Uchiyama, M., Sasahara, Y., Kaneko, T., Hashii, Y., Irie, M., Sato, A., Saito-Nanjo, Y., Funayama, R., Nagashima, T., Inoue, S., Nakayama, K., Ozono, K., Kure, S., Matsubara, Y., Imaizumi, M., Aoki, Y. Mutations in MECOM, encoding oncoprotein EVI1, cause radioulnar synostosis with amegakaryocytic thrombocytopenia. Am. J. Hum. Genet. 97: 848-854, 2015. [PubMed: 26581901] [Full Text: https://doi.org/10.1016/j.ajhg.2015.10.010]
Nucifora, G., Rowley, J. D. AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia. Blood 86: 1-14, 1995. [PubMed: 7795214]
Ogawa, S., Kurokawa, M., Tanaka, T., Mitani, K., Inazawa, J., Hangaishi, A., Tanaka, K., Matsuo, Y., Minowada, J., Tsubota, T., Yazaki, Y., Hirai, H. Structurally altered Evi-1 protein generated in the 3q21q26 syndrome. Oncogene 13: 183-191, 1996. [PubMed: 8700545]
Pekarsky, Y., Rynditch, A., Wieser, R., Fonatsch, C., Gardiner, K. Activation of a novel gene in 3q21 and identification of intergenic fusion transcripts with ecotropic viral insertion site I in leukemia. Cancer Res. 57: 3914-3919, 1997. [PubMed: 9307271]
Sugita, M., Yokokawa, Y., Yoneyama, H., Kaneko, T. A case of amegakaryocytic thrombocytopenia with radio-ulnar synostosis syndrome, successfully treated with allogeneic bone marrow transplantation. (Abstract) Haematologica 92 (s1): 280 only, 2007.
Yoshida, H., Hashii, Y., Okuda, T., Kusuki, S., Sato, E., Inoue, A., Kawakami, C., Yabe, M., Ohta, H., Ozono, K. A case of congenital bone marrow failure with radio-ulnar synostosis. (Letter) Int. J. Hemat. 91: 331-332, 2010. [PubMed: 20091385] [Full Text: https://doi.org/10.1007/s12185-010-0494-z]