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MLLT1  -  myeloid/lymphoid or mixed-lineage leukemia...

Homo sapiens

Synonyms: ENL, LTG19, Protein ENL, YEATS domain-containing protein 1, YEATS1
 
 
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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

 

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

 

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

References

  1. The leukemia-associated gene Mllt1/ENL: characterization of a murine homolog and demonstration of an essential role in embryonic development. Doty, R.T., Vanasse, G.J., Disteche, C.M., Willerford, D.M. Blood Cells Mol. Dis. (2002) [Pubmed]
  2. The oncogenic capacity of HRX-ENL requires the transcriptional transactivation activity of ENL and the DNA binding motifs of HRX. Slany, R.K., Lavau, C., Cleary, M.L. Mol. Cell. Biol. (1998) [Pubmed]
  3. Molecular analysis of t(11;19) breakpoints in childhood acute leukemias. Rubnitz, J.E., Behm, F.G., Curcio-Brint, A.M., Pinheiro, R.P., Carroll, A.J., Raimondi, S.C., Shurtleff, S.A., Downing, J.R. Blood (1996) [Pubmed]
  4. The mechanism of hematopoietic progenitor cell immortalization by MLL-ENL. Horton, S.J., Williams, O. Cell Cycle (2006) [Pubmed]
  5. Patterns of disease in localized extranodal lymphomas. Gospodarowicz, M.K., Sutcliffe, S.B., Brown, T.C., Chua, T., Bush, R.S. J. Clin. Oncol. (1987) [Pubmed]
  6. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Tkachuk, D.C., Kohler, S., Cleary, M.L. Cell (1992) [Pubmed]
  7. MLL-ENL cooperates with SCF to transform primary avian multipotent cells. Schulte, C.E., von Lindern, M., Steinlein, P., Beug, H., Wiedemann, L.M. EMBO J. (2002) [Pubmed]
  8. Molecular emergence of acute myeloid leukemia during treatment for acute lymphoblastic leukemia. Blanco, J.G., Dervieux, T., Edick, M.J., Mehta, P.K., Rubnitz, J.E., Shurtleff, S., Raimondi, S.C., Behm, F.G., Pui, C.H., Relling, M.V. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  9. Acute leukemias of different lineages have similar MLL gene fusions encoding related chimeric proteins resulting from chromosomal translocation. Corral, J., Forster, A., Thompson, S., Lampert, F., Kaneko, Y., Slater, R., Kroes, W.G., van der Schoot, C.E., Ludwig, W.D., Karpas, A. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  10. IgG antibody subclasses, tumor necrosis factor and IFN-gamma levels in patients with type II lepra reaction on thalidomide treatment. Partida-Sanchez, S., Favila-Castillo, L., Pedraza-Sanchez, S., Gomez-Melgar, M., Saul, A., Estrada-Parra, S., Estrada-Garcia, I. Int. Arch. Allergy Immunol. (1998) [Pubmed]
  11. Effect of one year clofazimine therapy on autonomic functions in lepromatous leprosy with lepra (ENL) reaction. Burte, N.P., Chandorkar, A.G., Muley, M.P., Balsara, J.J., Bulakh, P.M. Leprosy in India. (1983) [Pubmed]
  12. Levamisole in cases of E.N.L. Arora, S.K., Singh, G., Sen, P.C. Indian journal of leprosy. (1985) [Pubmed]
  13. Deep vein thrombosis: a rare complication of thalidomide therapy in recurrent erythema nodosum leprosum. Sharma, N.L., Sharma, V., Shanker, V., Mahajan, V.K., Sarin, S. Int. J. Lepr. Other Mycobact. Dis. (2004) [Pubmed]
  14. Serological study for presence of C-reactive protein, rheumatoid factor, anti streptolysin O in leprosy cases. Bhatia, V.N., Balakrishnan, S., Harikrishnan, S. Leprosy in India. (1983) [Pubmed]
  15. The HRX proto-oncogene product is widely expressed in human tissues and localizes to nuclear structures. Butler, L.H., Slany, R., Cui, X., Cleary, M.L., Mason, D.Y. Blood (1997) [Pubmed]
  16. Two distinct portions of LTG19/ENL at 19p13 are involved in t(11;19) leukemia. Yamamoto, K., Seto, M., Komatsu, H., Iida, S., Akao, Y., Kojima, S., Kodera, Y., Nakazawa, S., Ariyoshi, Y., Takahashi, T. Oncogene (1993) [Pubmed]
  17. The ENL moiety of the childhood leukemia-associated MLL-ENL oncoprotein recruits human Polycomb 3. García-Cuéllar, M.P., Zilles, O., Schreiner, S.A., Birke, M., Winkler, T.H., Slany, R.K. Oncogene (2001) [Pubmed]
  18. Complex MLL rearrangement in a patient with T-cell acute lymphoblastic leukemia. Chervinsky, D.S., Sait, S.N., Nowak, N.J., Shows, T.B., Aplan, P.D. Genes Chromosomes Cancer (1995) [Pubmed]
  19. Analysis of Acute Leukemias With MLL/ENL Fusion Transcripts: Identification of Two Novel Breakpoints in ENL. Fu, J.F., Liang, D.C., Shih, L.Y. Am. J. Clin. Pathol. (2007) [Pubmed]
  20. MLLT3 gene on 9p22 involved in t(9;11) leukemia encodes a serine/proline rich protein homologous to MLLT1 on 19p13. Iida, S., Seto, M., Yamamoto, K., Komatsu, H., Tojo, A., Asano, S., Kamada, N., Ariyoshi, Y., Takahashi, T., Ueda, R. Oncogene (1993) [Pubmed]
  21. Hoxa9 and Meis1 are key targets for MLL-ENL-mediated cellular immortalization. Zeisig, B.B., Milne, T., García-Cuéllar, M.P., Schreiner, S., Martin, M.E., Fuchs, U., Borkhardt, A., Chanda, S.K., Walker, J., Soden, R., Hess, J.L., Slany, R.K. Mol. Cell. Biol. (2004) [Pubmed]
  22. Characterization of t(11;19)(q23;p13.3) by fluorescence in situ hybridization analysis in a pediatric patient with therapy-related acute myelogenous leukemia. Cheng, L., Ramesh, K.H., Radel, E., Ratech, H., Wei, D., Cannizzaro, L.A. Cancer Genet. Cytogenet. (2001) [Pubmed]
  23. Oral zinc in recurrent Erythema Nodosum Leprosum reaction. Mathur, N.K., Bumb, R.A., Mangal, H.N. Leprosy in India. (1983) [Pubmed]
  24. The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin. Zeisig, D.T., Bittner, C.B., Zeisig, B.B., García-Cuéllar, M.P., Hess, J.L., Slany, R.K. Oncogene (2005) [Pubmed]
  25. Simultaneous localization of MLL, AF4 and ENL genes in interphase nuclei by 3D-FISH: MLL translocation revisited. Gué, M., Sun, J.S., Boudier, T. BMC Cancer (2006) [Pubmed]
  26. A RUNX/AML-binding motif residing in a novel 13-bp DNA palindrome may determine the expression of the proximal promoter of the human uPA gene. Kopf, E., Miskin, R. J. Thromb. Haemost. (2005) [Pubmed]
  27. Genes on chromosomes 4, 9, and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs. Nakamura, T., Alder, H., Gu, Y., Prasad, R., Canaani, O., Kamada, N., Gale, R.P., Lange, B., Crist, W.M., Nowell, P.C. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  28. Prospective randomized comparison of external dacryocystorhinostomy and endonasal laser dacryocystorhinostomy. Hartikainen, J., Grenman, R., Puukka, P., Seppä, H. Ophthalmology (1998) [Pubmed]
  29. Differences in predominant T cell phenotypes and distribution pattern in reactional lesions of tuberculoid and lepromatous leprosy. Narayanan, R.B., Laal, S., Sharma, A.K., Bhutani, L.K., Nath, I. Clin. Exp. Immunol. (1984) [Pubmed]
 
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