Alternative titles; symbols
HGNC Approved Gene Symbol: MLLT3
Cytogenetic location: 9p21.3 Genomic coordinates (GRCh38) : 9:20,341,669-20,622,499 (from NCBI)
Nakamura et al. (1993) cloned and sequenced cDNAs derived from transcripts of the AF4 (159557) and AF9 genes involved in the chromosome abnormalities t(4;11)(q21;q23) and t(9;11)(p22;q23), respectively. They found that the AF4 and AF9 genes, each of which fuses with the ALL1 gene (159555) in leukemia-associated translocations, show high sequence homology with the ENL gene (159556) 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, and ENL 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. The AF9 gene is also symbolized MLLT3.
Strissel et al. (2000) noted that the AF9 gene is more than 100 kb, and 2 patient breakpoint cluster regions (BCRs) have been identified; BCR1 is within intron 4, previously called site A, whereas BCR2 or site B spans introns 7 and 8. Strissel et al. (2000) defined the exon-intron boundaries and identified several different structural elements in AF9, including a colocalizing in vivo DNA topo II cleavage site and an in vitro DNase I hypersensitive (DNase 1 HS) site in intron 7 in BCR2. Reversibility experiments demonstrated a religation of the topo II cleavage sites. In addition, 2 scaffold associated regions (SARs) are located centromeric to the topo II and DNase I HS cleavage sites and border breakpoint regions in 2 leukemic cells lines: SAR1 is located in intron 4, whereas SAR2 encompasses parts of exons 5-7. The authors thus demonstrated that the patient breakpoint regions of AF9 share the same structural elements as the MLL BCR, and they proposed a DNA breakage and repair model for nonhomologous recombination between MLL and its partner genes, particularly AF9.
The human AF9 gene is one of the most common fusion partner genes with the ALL1 gene at 11q23 (also called MLL), resulting in the t(9;11)(p22;q23) (Nakamura et al., 1993; Strissel et al., 2000).
In a 6-year-old girl with neuromotor developmental delay, cerebellar ataxia, and epilepsy, Pramparo et al. (2005) identified a constitutional translocation t(4;9)(q35;p22) disrupting the MLLT3 gene. Pramparo et al. (2005) stated that this was the first report of the MLLT3 gene involved in a nonfusion balanced translocation, suggesting a haploinsufficiency model associated with this patient's phenotype.
Krivtsov et al. (2006) showed that leukemia stem cells can maintain the global identity of the progenitor from which they arose while activating a limited stem-cell- or self-renewal-associated program. They isolated leukemia stem cells from leukemias initiated in committed granulocyte macrophage progenitors through introduction of the MLL-AF9 fusion protein encoded by the t(9;11)(p22;q23). The leukemia stem cells were capable of transferring leukemia to secondary recipient mice when only 4 cells were transferred, and possessed an immunophenotype and global gene expression profile very similar to that of normal granulocyte macrophage progenitors. However, a subset of genes highly expressed in normal hematopoietic stem cells was reactivated in leukemic stem cells. Leukemic stem cells can thus be generated from committed progenitors without widespread reprogramming of gene expression, and a leukemia self-renewal-associated signature is activated in the process. Krivtsov et al. (2006) concluded that their findings define progression from normal progenitor to cancer stem cell, and suggest that targeting a self-renewal program expressed in an abnormal context may be possible.
Calvanese et al. (2019) identified MLLT3 as a crucial regulator of hematopoietic stem cells that is highly enriched in human fetal, neonatal, and adult hematopoietic stem cells, but downregulated in culture. Depletion of MLLT3 prevented the maintenance of transplantable human hematopoietic stem or progenitor cells in culture, whereas stabilizing MLLT3 expression in culture enabled more than 12-fold expansion of transplantable hematopoietic stem cells that provided balanced multilineage reconstitution in primary and secondary mouse recipients. Similar to endogenous MLLT3, overexpressed MLLT3 localized to active promoters in hematopoietic stem or progenitor cells, sustained levels of H3K79 dimethylation, and protected the hematopoietic stem cell transcriptional program in culture. MLLT3 thus acts as hematopoietic stem cell maintenance factor that links histone reader and modifying activities to modulate hematopoietic stem cell gene expression.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human MLLT3 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
Calvanese, V., Nguyen, A. T., Bolan, T. J., Vavilina, A., Su, T., Lee, L. K., Wang, Y., Lay, F. D., Magnusson, M., Crooks, G. M., Kurdistani, S. K., Mikkola, H. K. A. MLLT3 governs human haematopoietic stem-cell self-renewal and engraftment. Nature 576: 281-286, 2019. [PubMed: 31776511] [Full Text: https://doi.org/10.1038/s41586-019-1790-2]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Krivtsov, A. V., Twomey, D., Feng, Z., Stubbs, M. C., Wang, Y., Faber, J., Levine, J. E., Wang, J., Hahn, W. C., Gilliland, D. G., Golub, T. R., Armstrong, S. A. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442: 818-822, 2006. [PubMed: 16862118] [Full Text: https://doi.org/10.1038/nature04980]
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]
Pramparo, T., Grosso, S., Messa, J., Zatterale, A., Bonaglia, M. C., Chessa, L., Balestri, P., Rocchi, M., Zuffardi, O., Giorda, R. Loss-of-function mutation of the AF9/MLLT3 gene in a girl with neuromotor development delay, cerebellar ataxia, and epilepsy. Hum. Genet. 118: 76-81, 2005. [PubMed: 16001262] [Full Text: https://doi.org/10.1007/s00439-005-0004-1]
Strissel, P. L., Strick, R., Tomek, R. J., Roe, B. A., Rowley, J. D., Zeleznik-Le, N. J. DNA structural properties of AF9 are similar to MLL and could act as recombination hot spots resulting in MLL/AF9 translocations and leukemogenesis. Hum. Molec. Genet. 9: 1671-1679, 2000. [PubMed: 10861294] [Full Text: https://doi.org/10.1093/hmg/9.11.1671]