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Gene Review

MLLT3  -  myeloid/lymphoid or mixed-lineage leukemia...

Homo sapiens

Synonyms: AF-9, AF9, ALL1-fused gene from chromosome 9 protein, Myeloid/lymphoid or mixed-lineage leukemia translocated to chromosome 3 protein, Protein AF-9, ...
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Disease relevance of MLLT3

  • In the present study, we isolated chimeric cDNAs between the MLL and a gene designated MLLT3 at 9p22 from a cDNA library of an IMS-M1 cell line with a t(9;11)(p22;q23) translocation, a representative karyotypic abnormality seen in acute monocytic leukemia [1].
  • MLLT3, one of the genes shown to be a translocation breakpoint partner for the acute lymphocytic leukemia (MLL) gene, has been mapped to 9p22 [2].
  • 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 [3].
  • The 2 most frequent human MLL hematopoietic malignancies involve either AF4 or AF9 as fusion partners; each has distinct biology but the role of the fusion partner is not clear [4].
  • Here, data are presented demonstrating that MPc3 also interacts with AF9, a transcriptional activator implicated in the development of acute leukemias [5].

High impact information on MLLT3

  • Each of these tends to associate with a specific leukaemia type, for example, MLL-AF9 is found mainly in acute myeloid leukaemia [6].
  • Therefore, non-malignant expansion of myeloid precursors is the first stage of Mll-AF9-mediated leukaemia followed by accumulation of malignant cells in bone marrow and other tissues [6].
  • The amino-terminal half of MLL was sufficient for both cell cycle arrest and macrophage differentiation, whereas the carboxyl terminus of MLL or AF9 was found to be dispensable for this effect [7].
  • These results suggest that ALL1, AF4, and probably AF9 interact with the transcriptional machinery of the cell [8].
  • To begin studying this, we examined the All1, AF4, AF9, and AF17 proteins for the presence of potential transcriptional regulatory domains [8].

Chemical compound and disease context of MLLT3

  • Seventy-four subjects with hemagglutination inhibition antibody titers less than or equal to 16 against an attenuated influenza A virus AF9/Montreal/3/72 (H3N2) were randomly allocated to groups taking 0 (placebo), 25, 100, or 150 mg amantadine syrup prophylactically twice a day for 31 doses [9].

Biological context of MLLT3

  • We also isolated a normal MLLT3 cDNA and found an open reading frame encoding at least 318 amino acids with high serine/proline content (24.8%) [1].
  • The MLLT3 gene maps between D9S156 and D9S171 and contains an unstable polymorphic trinucleotide repeat [2].
  • We cloned and sequenced cDNAs derived from transcripts of the AF-4 and AF-9 genes involved in the most common chromosome abnormalities, t(4:11)(q21:q23) and t(9:11)(p22:q23), respectively [10].
  • In this study we used myeloid colony assays, immunophenotyping, and transplantation to evaluate myelopoiesis in Mll-AF9 mice [11].
  • Thus, in the monocytic lineage, MLL-AF9 may be expressed only in early phases and can induce deregulated amplification in both nonmalignant and malignant cells, maintaining the monocytic phenotype without blocking final maturation [12].

Anatomical context of MLLT3

  • Colony assays demonstrated that both prenatal and postnatal Mll-AF9 tissues have significantly increased numbers of CD11b(+)/CD117(+)/Gr-1(+/-) myeloid cells, often in compact clusters [11].
  • The C-terminal segment of AF9 spanning amino acids 478-568 transactivated transcription of the reporter gene in HeLa but not in NIH 3T3 cells [8].
  • Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9 [13].
  • We isolated LSC from leukaemias initiated in committed granulocyte macrophage progenitors through introduction of the MLL-AF9 fusion protein encoded by the t(9;11)(p22;q23) [13].
  • Therefore, the LSCs responsible for sustaining, expanding, and regenerating MLL-AF9 AML are downstream myeloid lineage cells, which have acquired an aberrant Hox-associated self-renewal program as well as other biologic features of hematopoietic stem cells [14].

Physical interactions of MLLT3

  • Finally, hPc3 binds to the C-terminus of AF9, another common MLL fusion partner [15].

Other interactions of MLLT3

  • The carboxy-terminal 84 amino acids of ENL, which encode two predicted helical structures highly conserved in AF9, were necessary and sufficient for transformation when they were fused to HRX [3].
  • Targeted down-regulation of MLL-AF9 with antisense oligodeoxyribonucleotide reduces the expression of the HOXA7 and -A10 genes and induces apoptosis in a human leukemia cell line, THP-1 [16].
  • The AF9 gene is >100 kb and two 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 [17].
  • DESIGN AND METHODS: Fluorescence in situ hybridization (FISH) was performed in two acute leukemias (AL), one acute myeloid leukemia (AML) M5a, and one treatment-related-AL (t-AL), to investigate the nature of complex changes accompanying the respective t(9;11)(p22;q23)-MLL/AF9 and t(11;16)(q23;p13.3)-MLL/CBP [18].
  • This is illustrated through an application to a candidate gene analysis of the MLLT3 gene in families with Alzheimer disease [19].

Analytical, diagnostic and therapeutic context of MLLT3

  • As previously found in t(11;19) leukemia, heterogeneous MLL-MLLT3 chimeric mRNAs could be detected by the reverse transcriptase-polymerase chain reaction (RT-PCR) in t(9;11) leukemia samples [1].
  • Northern blot analysis with the MLLT3 cDNA probe against normal tissues revealed multiple transcripts in lymphoid organs [1].
  • In the fifth patient, hematological CR could not be achieved with two cycles of intensive induction chemotherapy, and MLL-AF9 transcripts were present in all samples tested [20].
  • Two patients who had achieved hematological CR did not become PCR negative and MLL-AF9 fusion transcripts were detectable in all samples after induction and consolidation chemotherapy [20].


  1. 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]
  2. The MLLT3 gene maps between D9S156 and D9S171 and contains an unstable polymorphic trinucleotide repeat. Walker, G.J., Walters, M.K., Palmer, J.M., Hayward, N.K. Genomics (1994) [Pubmed]
  3. 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]
  4. A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematologic malignancy. Chen, W., Li, Q., Hudson, W.A., Kumar, A., Kirchhof, N., Kersey, J.H. Blood (2006) [Pubmed]
  5. The polycomb protein MPc3 interacts with AF9, an MLL fusion partner in t(9;11)(p22;q23) acute leukemias. Hemenway, C.S., de Erkenez, A.C., Gould, G.C. Oncogene (2001) [Pubmed]
  6. The mll-AF9 gene fusion in mice controls myeloproliferation and specifies acute myeloid leukaemogenesis. Dobson, C.L., Warren, A.J., Pannell, R., Forster, A., Lavenir, I., Corral, J., Smith, A.J., Rabbitts, T.H. EMBO J. (1999) [Pubmed]
  7. The amino terminus of the mixed lineage leukemia protein (MLL) promotes cell cycle arrest and monocytic differentiation. Caslini, C., Shilatifard, A., Yang, L., Hess, J.L. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  8. Domains with transcriptional regulatory activity within the ALL1 and AF4 proteins involved in acute leukemia. Prasad, R., Yano, T., Sorio, C., Nakamura, T., Rallapalli, R., Gu, Y., Leshkowitz, D., Croce, C.M., Canaani, E. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  9. Prophylactic amantadine dose and plasma concentration-effect relationships in healthy adults. Aoki, F.Y., Stiver, H.G., Sitar, D.S., Boudreault, A., Ogilvie, R.I. Clin. Pharmacol. Ther. (1985) [Pubmed]
  10. 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]
  11. Prenatal and postnatal myeloid cells demonstrate stepwise progression in the pathogenesis of MLL fusion gene leukemia. Johnson, J.J., Chen, W., Hudson, W., Yao, Q., Taylor, M., Rabbitts, T.H., Kersey, J.H. Blood (2003) [Pubmed]
  12. MLL-AF9 oncogene expression affects cell growth but not terminal differentiation and is downregulated during monocyte-macrophage maturation in AML-M5 THP-1 cells. Pession, A., Martino, V., Tonelli, R., Beltramini, C., Locatelli, F., Biserni, G., Franzoni, M., Freccero, F., Montemurro, L., Pattacini, L., Paolucci, G. Oncogene (2003) [Pubmed]
  13. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. 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. Nature (2006) [Pubmed]
  14. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Somervaille, T.C., Cleary, M.L. Cancer Cell (2006) [Pubmed]
  15. 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]
  16. Targeted down-regulation of MLL-AF9 with antisense oligodeoxyribonucleotide reduces the expression of the HOXA7 and -A10 genes and induces apoptosis in a human leukemia cell line, THP-1. Kawagoe, H., Kawagoe, R., Sano, K. Leukemia (2001) [Pubmed]
  17. DNA structural properties of AF9 are similar to MLL and could act as recombination hot spots resulting in MLL/AF9 translocations and leukemogenesis. Strissel, P.L., Strick, R., Tomek, R.J., Roe, B.A., Rowley, J.D., Zeleznik-Le, N.J. Hum. Mol. Genet. (2000) [Pubmed]
  18. Partial duplication of the MLL oncogene in patients with aggressive acute myeloid leukemia. Sambani, C., La Starza, R., Roumier, C., Crescenzi, B., Stavropoulou, C., Katsarou, O., Karafoulidou, A., Dhalle, J.H., Lai, J.L., Preudhomme, C., Martelli, M.F., Mecucci, C. Haematologica (2004) [Pubmed]
  19. Genotype-based association test for general pedigrees: the genotype-PDT. Martin, E.R., Bass, M.P., Gilbert, J.R., Pericak-Vance, M.A., Hauser, E.R. Genet. Epidemiol. (2003) [Pubmed]
  20. Monitoring of minimal residual leukemia in patients with MLL-AF9 positive acute myeloid leukemia by RT-PCR. Mitterbauer, G., Zimmer, C., Fonatsch, C., Haas, O., Thalhammer-Scherrer, R., Schwarzinger, I., Kalhs, P., Jaeger, U., Lechner, K., Mannhalter, C. Leukemia (1999) [Pubmed]
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