Disease relevance of Mll1

• This represents the first functional study using a knock-out strategy on one of the Mll partner genes in translocation-associated leukemias [1].
• In acute lymphoblastic leukemia associated with the t(4;11)(q21;q23) translocation, the 4q21 gene that fuses with Mll is AF4 [1].
• Chimeric mice carrying the fusion gene developed tumors, which were restricted to acute myeloid leukemias despite the widespread activity of the Mll promoter [2].
• Immortalized cells or enriched primary hematopoietic stem cells transduced with HRX-ENL induced myeloid leukemias in syngeneic and SCID recipients [3].
• A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematologic malignancy [4].

High impact information on Mll1

• An Mll-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: a method to create fusion oncogenes [2].
• The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene [5].
• The t(4;11) chromosome translocation results in two reciprocal fusion products coding for chimeric proteins derived from ALL-1 and from a gene on chromosome 4 [5].
• 11q23 translocations disrupt the HRX gene between these two motifs, and in a t(11;19)-carrying cell line fusion transcripts are expressed from both derivative chromosomes [6].
• Human trithorax (HRX) is a predicted 431 kd protein containing two potential DNA-binding motifs consisting of zinc fingers conserved with the fly protein and nonconserved amino-terminal "AT hook" motifs related to the DNA-binding motifs in HMG proteins [6].

Chemical compound and disease context of Mll1

• We synthesized a novel fluorescein isothiocyanate-labeled gadolinium-diethylenetriamine pentaacetic acid (DTPA) conjugate in which the commonly used gadolinium-DTPA complex is flanked by the nuclear localization sequences of the simian virus-40 T antigen and the acute lymphatic leukemia-1 (ALL-1) protein [7].

Biological context of Mll1

• Thus Mll is required for proper segment identity in mammals, displays haplo-insufficiency, and positively regulates Hox gene expression [8].
• Tumorigenesis in mice with a fusion of the leukaemia oncogene Mll and the bacterial lacZ gene [9].
• A subset of chromosomal translocations in acute leukemias results in the fusion of the trithorax-related protein HRX with a variety of heterologous proteins [3].
• Finally, we report that All-1 resides in the proximal portion of mouse chromosome 9 and is a candidate for a mutation that results in skeletal transformations during embryonic development [10].
• In addition, we have identified alternatively spliced forms of All-1 within one of the zinc-finger domains, suggesting that there may be different targets and/or functions for All-1 proteins [10].

Anatomical context of Mll1

• To characterize directly the potential transforming effects of HRX-ENL on primitive hematopoietic precursors, the fusion cDNA was transduced by retroviral gene transfer into cell populations enriched in hematopoietic stem cells [3].
• We have studied the role of the Mll-AF9 gene fusion made in mouse embryonic stem cells by an homologous recombination knock-in [11].
• We have used a model in which chromosomal translocations are generated in mice de novo by Cre-loxP-mediated recombination (translocator mice) to compare the functionally relevant haematopoietic cell contexts for Mll fusions, namely pluripotent stem cells, semicommitted progenitors or committed cells [12].
• However, while Mll-Enl translocations can also cause leukaemia from T-cell progenitors, no tumours arose with Mll-Af9 translocations in the T-cell compartment [12].
• Embryonic fibroblasts from Mll-deficient compared with Bmi-1-deficient mice demonstrate reciprocal regulation of Hox genes as well as an integrated Hoxc8-lacZ reporter construct [13].

Associations of Mll1 with chemical compounds

• By applying differential display to cultures of mouse fibroblast, we have identified two transcripts (acute lymphoblastic leukemia-1, All-1, and a novel gene named metal-responsive gene, MERE-1) that were responsive to platinum and cadmium ions [14].
• This antibody was shown to be highly effective in vitro at neutralizing the cytotoxic effects of mitozantrone for the acute leukaemia cell lines ALL-1 and MOLT4 [15].

Regulatory relationships of Mll1

• These alterations are enhanced by Zfp144 mutation but repressed by Mll mutation (a trithorax-group gene) [16].

Other interactions of Mll1

• Mll deficiency (-/-) was embryonic lethal [8].
• Immortalization and leukemic transformation of a myelomonocytic precursor by retrovirally transduced HRX-ENL [3].

Analytical, diagnostic and therapeutic context of Mll1

• Sequence analysis of the murine All-1 gene has identified distinct regions of homology with the human ALL-1 gene; these highly conserved domains may define regions of functional significance in mammals [10].
• Truncation of the Mll gene in exon 5 by gene targeting leads to early preimplantation lethality of homozygous embryos [17].
• Whole-mount in situ hybridization to early mouse embryos of 9.5-10.5 days indicated a complex pattern of Arp1 expression spatially overlapping with the expression of All1 [18].
• We detected Mll fusions at a higher frequency following 100 microM etoposide for 8 h (16x10(-6) cell(-1)) than in no-drug controls (1.0x10(-6) cell(-1), P=0.0002) or after treatment with a comparably cytotoxic exposure to the antimicrotubule drug vincristine (1.0x10(-6) cell(-1), P=0.0047) [19].
• To determine whether Mll genomic fusions can occur after exposure to topoisomerase II inhibitors, we developed a long-distance inverse PCR DNA-based assay for chimeric Mll fusions in mouse embryonic stem cells [19].

References