Disease relevance of MLLT1

• These studies indicate that MLLT1 is involved in essential developmental processes and suggest that expression patterns of MLL fusion partners may influence the lineage of MLL-associated leukemias [1].
• Two of these partners, ENL and AF9, code for proteins that are highly similar to each other and as fusions with HRX induce myeloid leukemias in mice as demonstrated by retroviral gene transfer and knock-in experiments, respectively [2].
• All 17 cases of acute lymphoblastic leukemia (ALL) had MLL/ENL fusion transcripts [3].
• The t(11;19) translocation gives rise to the MLL-ENL fusion protein and is frequently found in infant myeloid and lymphoid leukemias [4].
• GALT lymphomas (GALT-L) have a survival advantage compared with other ENL (P = .017) independent of stage and histology [5].

High impact information on MLLT1

• The more abundant derivative 11 transcript codes for a chimeric protein containing the AT hook motifs fused to a previously undescribed protein (ENL) from chromosome 19 [6].
• Finally, in cooperation with the weakly leukaemogenic receptor tyrosine kinase v-Sea, the MLL-ENL fusion protein gave rise to multilineage leukaemia in chicks, suggesting that other activated, receptor tyrosine kinases can substitute for ligand-activated c-Kit in vivo [7].
• At the first detection of MLL-ENL, the only topoisomerase II inhibitors the patient had received were one dose of daunorubicin and two doses of etoposide [8].
• The mRNA translocation junction from 22 t(4;11) patients, including six adult leukemias, and nine t(11;19) tumors reveals a remarkable conservation of breakpoints within MLL, AF4, or ENL genes, irrespective of tumor phenotype [9].
• Partial sequence of a fusion between MLL and the AFX1 gene from chromosome X shows the latter to be rich in Ser/Pro codons, like the ENL mRNA [9].

Chemical compound and disease context of MLLT1

• A group of 9 Mexican lepromatous leprosy patients was studied at the beginning of a type II reaction (erythema nodosum leprosum, ENL) and after 1 or 2 months of thalidomide treatment [10].
• Effect of one year clofazimine therapy on autonomic functions in lepromatous leprosy with lepra (ENL) reaction [11].
• Levamisole, the anthelmintic drug was tried in ENL (Erythema Nodosum Leprosum) cases using double blind control trial in dosage of 150 mg/day on three consecutive days for three months [12].
• A case of deep-vein thrombosis is reported in a female patient with multibacillary leprosy who received pulses of dexamethasone and cyclophosphamide for recurrent ENL that had not responded to prednisone and thalidomide [13].
• Serological tests for the detection of C-reactive protein (CRP), Rheumatoid factor (RE) and Anti Streptolysin 'O' (ASLO) antibodies employing latex test were carried out in 120 cases of active lepromatous leprosy, 14 LL cases with ENL during active and subsided phases and 25 controls [14].

Biological context of MLLT1

• Similarly, mutations that deleted one or both of these conserved helices completely abrogated the transcriptional activation properties of ENL [2].
• The specificity of these reagents was confirmed using cells transfected with the HRX-ENL fusion gene [15].
• Deletions of either the AT hook motifs or the methyltransferase homology domain of HRX substantially impaired the transforming effects of HRX-ENL [2].
• To elucidate the molecular basis for the heterogeneity, we isolated cDNA clones of a translocation-associated gene on chromosome 19, LTG19, as well as chimeric cDNAs from KOPN-1 [16].
• This event truncates the proto-oncogene MLL and fuses the 5' end of MLL in frame with the ENL gene [17].

Anatomical context of MLLT1

• In the present study, a structure-function analysis was performed to determine the molecular requirements for in vitro immortalization of murine myeloid cells by HRX-ENL [2].
• Northern analysis with LTG19 cDNA demonstrated the identical gene, encoding serine/proline rich 559 amino acid polypeptide, to be involved in all three cell lines [16].
• Additionally, this report provides the first conclusive evidence of an MLL/ENL gene fusion characterized at a molecular level in a patient with T-cell ALL [18].
• The MLL-ENL fusion was not detectable in bone marrow at the time of ALL diagnosis or after 2 months of chemotherapy (frequency <8.3 x 10(-7) cells(-1)) [8].
• Of 15 patients with MLL/ENL, 7 had precursor B-cell acute lymphoblastic leukemia, 4 had T-cell acute lymphoblastic leukemia, and 4 had acute myeloid leukemia [19].

Associations of MLLT1 with chemical compounds

• MLLT3 gene on 9p22 involved in t(9;11) leukemia encodes a serine/proline rich protein homologous to MLLT1 on 19p13 [20].
• We constructed an inducible MLL fusion, MLL-ENL-ERtm, that rendered the transcriptional and transforming properties of MLL-ENL strictly dependent on the presence of 4-hydroxy-tamoxifen [21].
• However, the breakpoint in 19p is variable in that it could be located either at 19p13.1 or 19p13.3 and thus could involve either of two genes: ELL (11-19 lysine-rich leukemia gene) on 19p13.1 or ENL (11-19 leukemia gene) on 19p13 [22].
• Serum IFN-gamma was significantly lower in patients at the onset of ENL and was increased after 1 and 2 months of thalidomide treatment [10].
• To control ENL, they required high dosage of clofazimine and steroids for prolonged periods [23].

Physical interactions of MLLT1

• The methyltransferase homology domain was shown to bind non-sequence specifically to DNA in vitro, providing evidence that the full transforming activity of HRX-ENL requires multiple DNA binding structures in HRX [2].
• An internal region of hPc3 was responsible for binding to ENL [17].
• In two-hybrid studies, ENL interacted with AF4 and AF5q31 as well as with a fragment of AF10 [24].

Other interactions of MLLT1

• The ENL-hPc3 interaction was verified by mutual co-precipitation of the proteins from cell extracts [17].
• RESULTS: In all cell lines, the ENL gene is significantly closer to the MLL gene than the AF4 gene (with P value < 0.0001) [25].
• These data suggest that the majority of 11;19 translocations involve ENL, whereas involvement of ELL is relatively uncommon in childhood acute leukemia and may be restricted to AML [3].
• The palindrome was found in five additional human genes, two of which (MYH11 and MLLT1) have been linked to chromosomal rearrangements leading to leukemia [26].
• Immortalized myeloid cell lines can be generated by expression of MLL-ENL in murine hematopoietic progenitors [4].

Analytical, diagnostic and therapeutic context of MLLT1

• Sequence analysis indicates high homology between the AF-9 gene protein product and the protein encoded by the ENL gene fused to ALL-1 in (11:19) chromosome translocations [27].
• We used PCR with patient-specific genomic primers to establish the emergence of the MLL-ENL fusion in serially obtained DNA samples [8].
• We therefore used reverse transcriptase-polymerase chain reaction (RT-PCR) assays to analyze 26 cases of childhood acute leukemia containing t(11;19) to determine the frequencies of ENL and ELL involvement [3].
• OBJECTIVE AND DESIGN: The introduction of endonasal laser dacryocystorhinostomy (ENL-DCR) in the early 1990s showed great promise of changing dacryocystorhinostomy into an elegant, minimally invasive procedure from the traditional external dacryocystorhinostomy (EXT-DCR) [28].
• The nature and histological pattern of the cutaneous infiltrates of 17 leprosy patients in reversal reactions (Type I) and erythema nodosum leprosum (Type II, ENL) were compared with tissues from 18 non-reactional borderline leprosy (BT, BL) and lepromatous leprosy (LL) patients using monoclonal antibodies and immunofluorescence [29].

References