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HGNC Approved Gene Symbol: MLLT1
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38) : 19:6,210,381-6,279,975 (from NCBI)
Tkachuk et al. (1992) showed that the gene involved in recurring 11q23 leukemogenic translocations codes for an unusually large protein that is a homolog of Drosophila 'trithorax' and is involved in homeotic gene regulation (MLL; 159555). In studies of a t(11;19) translocation, they identified a chimeric protein containing the amino-terminal 'AT-hook' motifs of the MLL gene on chromosome 11 fused to a previously undescribed protein from chromosome 19. The nucleotide sequence determinations demonstrated an open reading frame that coded for a predicted 62-kD protein, which Tkachuk et al. (1992) named ENL for 'eleven-nineteen leukemia.'
Nakamura et al. (1993) showed that the gene on chromosome 19 that is fused to the MLL gene (also known as ALL1 gene) in patients with leukemia and translocation t(11;19)(q23;p13) shows high sequence homology to the genes on chromosome 4 (159557) and chromosome 9 (159558) that are fused with the ALL1 gene in patients with translocation t(4;11)(q21;q23) and t(9;11)(p22;q23), respectively. The 3 protein gene products contained nuclear targeting sequences as well as serine-rich and proline-rich regions.
Thirman et al. (1994) stated that the MLLT1 gene maps to chromosome 19p13.3.
Rubnitz et al. (1994) characterized the transcriptional transactivation properties of ENL. It is a nuclear protein that is capable of activating transcription from synthetic reporter genes in both lymphoid and myeloid cells, as well as in yeast. Deletion mutagenesis demonstrated that the minimal portion of the gene required for activation of transcription was located to its C-terminal 90 amino acids. This region is highly conserved between ENL and the t(9;11) fusion partner AF9 (MLLT3) and is retained in all fusion proteins.
By gel filtration, mass spectrometry, and Western blot analysis of human cell lines, Nie et al. (2003) identified unique low-abundance SWI/SWF complexes that contained ENL, several common SWI/SNF subunits, and either BAF250A (ARID1A; 603024) or BAF250B (ARID1B; 614556). Western blot analysis of HB(11;19) leukemia cells, which express the oncogenic MLL/ENL fusion protein, revealed that MLL/ENL also interacted with the BAF250B-containing complex. MLL/ENL-containing SWI/SNF complexes coactivated the HOXA7 (142950) promoter in a reporter gene assay.
Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs. Recognition of modified histones by 'reader' proteins constitutes a key mechanism underlying these processes. Wan et al. (2017) showed that the YEATS domain-containing protein ENL (MLLT1), but not its paralog AF9 (MLLT3; 159558), is required for disease maintenance in acute myeloid leukemia. CRISPR-Cas9-mediated depletion of ENL led to antileukemic effects, including increased terminal myeloid differentiation and suppression of leukemia growth in vitro and in vivo. Biochemical and crystal structural studies and chromatin-immunoprecipitation followed by sequencing analyses revealed that ENL binds to acetylated histone H3 (see 602810) and colocalizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukemia. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced the recruitment of RNA polymerase II (see 180660) to ENL target genes, leading to the suppression of oncogenic gene expression programs. Notably, disrupting the functionality of ENL further sensitized leukemia cells to bromodomain and extra-terminal (BET) inhibitors. Wan et al. (2017) concluded that their data identified ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in acute myeloid leukemia, and suggested that displacement of ENL from chromatin may be a promising epigenetic therapy, alone or in combination with BET inhibitors, for aggressive leukemia.
Recurrent chromosomal translocations producing a chimeric MLL oncogene give rise to a highly aggressive acute leukemia associated with poor clinical outcome. The preferential involvement of chromatin-associated factors as MLL fusion partners belies a dependency on transcription control. Erb et al. (2017) used unbiased CRISPR-Cas9 technology to perform a genome-scale loss-of-function screen in an MLL-AF4 (159557)-positive acute leukemia cell line and identified ENL as an unrecognized gene that is specifically required for proliferation in vitro and in vivo. To explain the mechanistic role of ENL in leukemia pathogenesis and dynamic transcription control, a chemical genetic strategy was developed to achieve targeted protein degradation. Acute loss of ENL suppressed the initiation and elongation of RNA polymerase II at active genes genome-wide, with pronounced effects at genes featuring a disproportionate ENL load. Notably, an intact YEATS chromatin-reader domain was essential for ENL-dependent leukemic growth. Erb et al. (2017) concluded that their findings identified a dependency factor in acute leukemia and suggested a mechanistic rationale for disrupting the YEATS domain in disease.
Thirman et al. (1994) pointed out that the breakpoint that results in the fusion of MLL to the ENL gene is located at 19p13.3. Another translocation t(11;19)(q23;p13.1) results in fusion of the MLL gene with the ELL gene (600284) in acute myeloid leukemia. This gene is also symbolized MLLT1.
Recurrent heterozygous somatic mutations clustered in the YEATS domain of the ENL protein have been identified in Wilms tumor. These hotspot mutations all involve small in-frame insertions or deletions. Wan et al. (2020) used human and mouse cells to demonstrate that these mutations impair cell fate regulation by conferring gain of function in chromatin recruitment and transcriptional control. ENL mutants induced gene expression changes that favor a premalignant cell fate, and, in an assay for nephrogenesis using murine cells, resulted in undifferentiated structures resembling those observed in human Wilms tumor.
Erb, M. A., Scott, T. G., Li, B. E., Xie, H., Paulk, J., Seo, H.-S., Souza, A., Roberts, J. M., Dastjerdi, S., Buckley, D. L., Sanjana, N. E., Shalem, O., Nabet, B., Zeid, R., Offei-Addo, N. K., Dhe-Paganon, S., Zhang, F., Orkin, S. H., Winter, G. E., Bradner, J. E. Transcription control by the ENL YEATS domain in acute leukaemia. Nature 543: 270-274, 2017. [PubMed: 28241139] [Full Text: https://doi.org/10.1038/nature21688]
Nakamura, T., Alder, H., Gu, Y., Prasad, R., Canaani, O., Kamada, N., Gale, R. P., Lange, B., Crist, W. M., Nowell, P. C., Croce, C. M., Canaani, E. Genes on chromosomes 4, 9, and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs. Proc. Nat. Acad. Sci. 90: 4631-4635, 1993. [PubMed: 8506309] [Full Text: https://doi.org/10.1073/pnas.90.10.4631]
Nie, Z., Yan, Z., Chen, E. H., Sechi, S., Ling, C., Zhou, S., Xue, Y., Yang, D., Murray, D., Kanakubo, E., Cleary, M. L., Wang, W. Novel SWI/SNF chromatin-remodeling complexes contain a mixed-lineage leukemia chromosomal translocation partner. Molec. Cell. Biol. 23: 2942-2952, 2003. [PubMed: 12665591] [Full Text: https://doi.org/10.1128/MCB.23.8.2942-2952.2003]
Rubnitz, J. E., Morrissey, J., Savage, P. A., Cleary, M. L. ENL, the gene fused with HRX in t(11;19) leukemias, encodes a nuclear protein with transcriptional activation potential in lymphoid and myeloid cells. Blood 84: 1747-1752, 1994. [PubMed: 8080983]
Thirman, M. J., Levitan, D. A., Kobayashi, H., Simon, M. C., Rowley, J. D. Cloning of ELL, a gene that fuses to MLL in a t(11;19)(q23;p13.1) in acute myeloid leukemia. Proc. Nat. Acad. Sci. 91: 12110-12114, 1994. [PubMed: 7991593] [Full Text: https://doi.org/10.1073/pnas.91.25.12110]
Tkachuk, D. C., Kohler, S., Cleary, M. L. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell 71: 691-700, 1992. [PubMed: 1423624] [Full Text: https://doi.org/10.1016/0092-8674(92)90602-9]
Wan, L., Chong, S., Xuan, F., Liang, A., Cui, X., Gates, L., Carroll, T. S., Li, Y., Feng, L., Chen, G., Wang, S.-P., Ortiz, M. V., and 11 others. Impaired cell fate through gain-of-function mutations in a chromatin reader. Nature 577: 121-126, 2020. [PubMed: 31853060] [Full Text: https://doi.org/10.1038/s41586-019-1842-7]
Wan, L., Wen, H., Li, Y., Lyu, J., Xi, Y., Hoshii, T., Joseph, J. K., Wang, X., Loh, Y.-H. E., Erb, M. A., Souza, A. L., Bradner, J. E., Shen, L., Li, W., Li, H., Allis, C. D., Armstrong, S. A., Shi, X. ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia. Nature 543: 265-269, 2017. [PubMed: 28241141] [Full Text: https://doi.org/10.1038/nature21687]