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HGNC Approved Gene Symbol: AFF1
Cytogenetic location: 4q21.3-q22.1 Genomic coordinates (GRCh38): 4:86,935,011-87,141,039 (from NCBI)
The ALL1 gene (MLL; 159555), located at 11q23, is rearranged in acute leukemias with reciprocal translocations between this region and chromosomes 1, 4, 6 (159559), 9 (159558), 10, or 19 (159556). Gu et al. (1992) studied the t(4;11) translocation which results in 2 reciprocal fusion products coding for chimeric proteins derived from ALL1 and from a gene on chromosome 4. They referred to the latter as AF4 for 'ALL1-fused gene from chromosome 4.' Fused RNAs were found in the three t(4;11) cells lines studied; therefore, Gu et al. (1992) could not establish which of the 2 products is oncogenic.
Nakamura et al. (1993) found that the gene on chromosome 4q21 that is fused with the ALL1 gene in patients with acute lymphoblastic leukemia and translocation t(4;11)(q21;q23) and the gene on chromosome 9 that is fused with the ALL1 gene on chromosome 11 in patients with leukemia and the t(9;11)(p22;q23) show high sequence homology with the ENL gene on chromosome 19, which is fused to the ALL1 gene in patients with leukemia and the translocation t(11;19)(q23;p13). They found further that the protein products of the AF4, AF9 (MLLT3), and ENL (MLLT1) genes contained nuclear targeting sequences as well as serine-rich and proline-rich regions. Stretches abundant in basic amino acids were also present in the 3 proteins. These results indicated that the different proteins fused to ALL1 polypeptides in leukemia provide similar functional domains.
Domer et al. (1993) independently demonstrated that the derivative chromosome 11, carrying a translocated segment of chromosome 4, encodes a fusion RNA which predicts a chimeric protein with features of the MLL gene on 11q23 and the AF4 gene on 4q21. The sequence of the complete open reading frame for this fusion transcript revealed that the MLL protein is homologous with DNA methyltransferase, the Drosophila trithorax gene product, and the 'AT-hook' motif of high mobility group proteins. An alternative splice that deletes the AT-hook region of MLL was identified. AF4 is a serine- and proline-rich putative transcription factor with a glutamine-rich carboxyl terminus. The composition of the complete MLL-AF4 fusion product argues that it may act through either a gain-of-function or a dominant-negative mechanism in leukemogenesis. This gene is also symbolized MLLT2.
Isnard et al. (1998) isolated cDNA clones of the mouse Af4 gene. By Northern analysis, they detected a single transcript of approximately 10 kb in all adult tissues examined, with highest expression in thymus, lymph nodes, and kidney. They also studied expression in fetal thymus and liver.
Gu et al. (1992) identified the AF4 gene on chromosome 4q21.
By fluorescence in situ hybridization, Isnard et al. (1998) showed that the Af4 gene maps to the E region of mouse chromosome 5, which is syntenic with human 4q21.
AFF1/MLL Fusion Gene
Uckun et al. (1998) analyzed bone marrow leukemic cells of 17 infants and 127 children with newly diagnosed acute lymphatic leukemia (ALL), as well as fetal liver and bone marrow and normal infant bone marrow samples for the presence of a t(4;11) translocation, using standard cytogenetic techniques and expression of an MLL-AF4 fusion transcript by standard RT-PCR assays as well as nested RT-PCR that is 100-fold more sensitive than the standard RT-PCR. Overall, 9 of the 17 infants and 17 of 127 noninfant pediatric ALL patients were positive for expression of MLL-AF4 fusion transcripts. None of the MLL-AF4(+) cases were positive for E2A-PBX1 (147141; 176310) or BCR-ABL (151410; 189980) fusion transcript expression. Although 8 of 9 MLL-AF4(+) infants had cytogenetically detectable t(4;11) translocation, 15 of the 17 MLL-AF4(+) noninfants were t(4;11) negative. Infants with MLL-AF4(+) ALL had poor outcomes, whereas noninfant fusion-gene-positive, translocation-negative patients has favorable outcomes similar to MLL-AF4(-) patients. Notably, MLL-AF4 transcripts also were detected by nested RT-PCR in 4 of 16 fetal bone marrows, 5 of 13 fetal livers, and 1 of 6 normal infant bone marrows, but not in any of the 44 remission bone marrow specimens from pediatric ALL patients. These results represented unprecedented evidence that MLL-AF4 fusion transcripts can be present in normal hematopoietic cells, indicating that their expression is insufficient for leukemic transformation of normal lymphocyte precursors.
To gain insight into the translocation mechanism and the relevant drug exposure in treatment-related leukemia, Lovett et al. (2001) analyzed the der(11) and der(4) genomic breakpoint junctions of a t(4;11) translocation in the leukemia of a patient previously administered etoposide and dactinomycin for the chemotherapy of primary alveolar rhabdomyosarcoma (268220). The genomic breakpoint junctions involved intron 6 of the MLL gene and intron 3 of the AF4 gene. Recombination was precise at the sequence level except for the overall gain of a single templated nucleotide. The translocation breakpoints in MLL and AF4 were DNA topoisomerase II cleavage sites. Etoposide and its metabolites, but not dactinomycin, enhanced cleavage at these sites on in vitro incubation. The findings were inconsistent with a translocation mechanism involving interchromosomal recombination by simple exchange of DNA topoisomerase II subunits and DNA-strand transfer. Etoposide and/or its metabolites were considered the relevant exposures in this patient.
Domer, P. H., Fakharzadeh, S. S., Chen, C.-S., Jockel, J., Johansen, L., Silverman, G. A., Kersey, J. H., Korsmeyer, S. J. Acute mixed-lineage leukemia t(4;11)(q21;q23) generates an MLL-AF4 fusion product. Proc. Nat. Acad. Sci. 90: 7884-7888, 1993. [PubMed: 7689231] [Full Text: https://doi.org/10.1073/pnas.90.16.7884]
Gu, Y., Nakamura, T., Alder, H., Prasad, R., Canaani, O., Cimino, G., Croce, C. M., Canaani, E. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell 71: 701-708, 1992. [PubMed: 1423625] [Full Text: https://doi.org/10.1016/0092-8674(92)90603-a]
Isnard, P., Depetris, D., Mattei, M.-G., Ferrier, P., Djabali, M. cDNA cloning, expression and chromosomal localization of the murine AF-4 gene involved in human leukemia. Mammalian Genome 9: 1065-1068, 1998. [PubMed: 9880680] [Full Text: https://doi.org/10.1007/s003359900927]
Lovett, B. D., Lo Nigro, L., Rappaport, E. F., Blair, I. A., Osheroff, N., Zheng, N., Megonigal, M. D., Williams, W. R., Nowell, P. C., Felix, C. A. Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation. Proc. Nat. Acad. Sci. 98: 9802-9807, 2001. [PubMed: 11493704] [Full Text: https://doi.org/10.1073/pnas.171309898]
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]
Uckun, F. M., Herman-Hatten, K., Crotty, M.-L., Sensel, M. G., Sather, H. N., Tuel-Ahlgren, L., Sarquis, M. B., Bostrom, B., Nachman, J. B., Steinherz, P. G., Gaynon, P. S., Heerema, N. Clinical significance of MLL-AF4 fusion transcript expression in the absence of a cytogenetically detectable t(4;11)(q21;q23) chromosomal translocation. Blood 92: 810-821, 1998. [PubMed: 9680349]