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HGNC Approved Gene Symbol: MLLT10
Cytogenetic location: 10p12.31 Genomic coordinates (GRCh38) : 10:21,533,756-21,743,630 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p12.31 | Leukemia, acute myeloid | 601626 | Autosomal dominant; Somatic mutation | 3 |
MLLT10 functions as a cofactor in a protein complex with DOT1L (607375), a methyltransferase that activates gene expression by monomethylation of lys79 of histone H3 (see 602810) (Ogoh et al., 2017).
Translocations affecting chromosome 11q23 involve many partner chromosome regions and occur in various leukemias (see 600328). The 11q23 gene involved in the translocations is MLL (159555). Using RACE to identify MLL fusion transcripts in RNA from 2 leukemia patients, Chaplin et al. (1995) identified the partner gene involved in t(10;11)(p12;q23) translocations. In both patients, the translocation fused MLL to a gene that the authors designated AF10. The AF10 gene encodes a predicted 1,027-amino acid protein containing an N-terminal zinc finger and a C-terminal leucine zipper domain that are highly homologous to similar domains in AF17 (600328) and BR140 (602410). Northern blot analysis showed that AF10 is expressed as a 5.5-kb mRNA in many tissues with highest expression in testis, and has an alternatively spliced exon.
By in situ hybridization, Ogoh et al. (2017) found that Mllt10 was dynamically expressed in whole mouse embryo. Mllt10 mRNA was detected throughout the embryo in a spatiotemporally restricted pattern, with highest expression in primordia of developing face, jaw, and limbs. In craniofacial tissue, Mllt10 was expressed in both mesenchyme and epithelium.
Chaplin et al. (1995) used fluorescence in situ hybridization to map the AF10 gene to 10p12.
The AF10 gene is one of the few MLL partner genes to be independently rearranged with a third gene in leukemia, the CALM gene (603025) in the t(10;11)(p12;q14) translocation (Dreyling et al., 1996). Chimeric fusion proteins MLL/AF10 and CALM/AF10 consistently retain the leucine zipper motif of AF10. Debernardi et al. (2002) used this part of the C-terminal region as bait in a yeast 2-hybrid screening of a testis cDNA library. They found that the leucine zipper interacted with GAS41 (602116), a protein previously identified as the product of an amplified gene in a glioblastoma. GAS41 shows significant homology to the human MLL fusion partners AF9 (159558) and ENL (159556). The study also showed that GAS41 interacts with integrase interactor-1 (INI1; 601607) and that INI1 is a component of the SWI/SNF complex (see 604958), which acts to remodel chromatin and to modulate transcription. Retention of the leucine zipper in the MLL and CALM fusions suggested that a key feature of these chimeric proteins may be their ability to interfere in normal gene regulation through interaction with the adenosine triphosphate-dependent chromatin remodeling complexes.
AF10/MLL Fusion Gene
Chaplin et al. (1995) found that all known translocations involving MLL and AF10 or AF17 have involved breakpoints between the zinc finger and leucine zipper domains, and have yielded fusion proteins in which the MLL zinc fingers were replaced with leucine zipper regions. Chaplin et al. (1995) speculated that the fusion proteins may participate in abnormal heterodimers.
AF10/HEAB Fusion Gene
Tanabe et al. (1996) identified an invins(10;11)(p12;q23q12) and other complex chromosomal rearrangements in a 2-year old boy with acute monoblastic leukemia (AML-M5). Cloning of the proximal 10p breakpoint showed that the MLL gene at chromosome 11q23 was fused to the 3-prime portion of AF10 at chromosome 10p12. Cloning of the telomeric 10p junction revealed that the 5-prime portion of AF10 was fused with the HEAB gene (608757). The 5-prime AF10/HEAB fusion transcript was out of frame, while the MLL/3-prime AF10 transcript was in frame.
For a discussion of a possible association between variation in the MLLT10 gene and susceptibility to meningioma, see 607174.
Ogoh et al. (2017) found no deficits in mice heterozygous for an Mllt10 null mutation. However, Mllt10 -/- mice died around embryonic day 13.5 (E13.5) due to vascular defects, with severe midline facial clefting and ocular hypertelorism. Mllt10 -/- mice also showed reduced H3K79 dimethylation in developing nasal processes, reduced expression of Ap2-alpha (TFAP2A; 107580) and Six2 (604994), and reduced cell proliferation in midline. However, they showed increased proliferation in neural progenitor cells, causing forebrain expansion. Pharmacologic inhibition of Dot1l in cultured E9.5 whole mouse embryos resulted in findings at E10.5 that were similar to, but more severe than, those of Mllt10 -/- mice.
Chaplin, T., Ayton, P., Bernard, O. A., Saha, V., Della Valle, V., Hillion, J., Gregorini, A., Lillington, D., Berger, R., Young, B. D. A novel class of zinc finger/leucine zipper genes identified from the molecular cloning of the t(10;11) translocation in acute leukemia. Blood 85: 1435-1441, 1995. [PubMed: 7888665]
Debernardi, S., Bassini, A., Jones, L. K., Chaplin, T., Linder, B., de Bruijn, D. R. H., Meese, E., Young, B. D. The MLL fusion partner AF10 binds GAS41, a protein that interacts with the human SWI/SNF complex. Blood 99: 275-281, 2002. [PubMed: 11756182] [Full Text: https://doi.org/10.1182/blood.v99.1.275]
Dreyling, M. H., Martinez-Climent, J. A., Zheng, M., Mao, J., Rowley, J. D., Bohlander, S. K. The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 gene and CALM, encoding a new member of the AP-3 clathrin assembly protein family. Proc. Nat. Acad. Sci. 93: 4804-4809, 1996. [PubMed: 8643484] [Full Text: https://doi.org/10.1073/pnas.93.10.4804]
Ogoh, H., Yamagata, K., Nakao, T., Sandell, L. L., Yamamoto, A., Yamashita, A., Tanga, N., Suzuki, M., Abe, T., Kitabayashi, I., Watanabe, T., Sakai, D. Mllt10 knockout mouse model reveals critical role of Af10-dependent H3K79 methylation in midfacial development. Sci. Rep. 7: 11922, 2017. Note: Electronic Article. [PubMed: 28931923] [Full Text: https://doi.org/10.1038/s41598-017-11745-5]
Tanabe, S., Bohlander, S. K., Vignon, C. V., Espinosa, R., III, Zhao, N., Strissel, P. L., Zeleznik-Le, N. J., Rowley, J. D. AF10 is split by MLL and HEAB, a human homolog to a putative Caenorhabditis elegans ATP/GTP-binding protein in an invins(10;11)(p12;q23q12). Blood 88: 3535-3545, 1996. [PubMed: 8896421]