Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009 Jul;94(7):984-93.
doi: 10.3324/haematol.2008.002436. Epub 2009 Jun 16.

The molecular biology of mixed lineage leukemia

Robert K Slany  1
Affiliations
Review

The molecular biology of mixed lineage leukemia

Robert K Slany. Haematologica. 2009 Jul.

Abstract

Mixed lineage leukemia is a very aggressive blood cancer that predominantly occurs in pediatric patients. In contrast to other types of childhood acute leukemias, mixed lineage leukemia presents with a dismal prognosis and despite the availability of advanced treatment methods cure rates have stagnated over the last years. Mixed lineage leukemia is characterized by the presence of MLL fusion proteins that are the result of chromosomal translocations affecting the MLL gene at 11q23. These events juxtapose the amino-terminus of the histone methyltransferase MLL with a variety of different fusion partners that destroy normal histone methyltransferase function of MLL and replace it by heterologous functions contributed by the fusion partner. The resulting chimeras are transcriptional regulators that take control of targets normally controlled by MLL with the clustered HOX homeobox genes as prominent examples. Recent studies suggested that MLL fusion partners activate transcription by two different mechanisms. Some of these proteins are themselves chromatin modifiers that introduce histone acetylation whereas other fusion partners can recruit histone methyltransferases. In particular, histone H3 specific methylation at lysine 79 catalyzed by DOT1L has been recognized as a hallmark of chromatin activated by MLL fusion proteins. Interestingly, several frequent MLL fusion partners seem to coordinate DOT1L activity with a protein complex that stimulates the elongation phase of transcription by phosphorylating the carboxy-terminal repeat domain of RNA polymerase II. The discovery of these novel enzymatic activities that are essentially involved in MLL fusion protein function presents potential new targets for a rational drug development.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Event free survival of infants with ALL separated by MLL status. Redrawn after Hilden et al. Please note that the data correspond to event free survival (a more stringent criterion) and do not include children older than one year.
Figure 2.
Figure 2.
The MLL complex. After post-transcriptional proteolytic processing amino-terminal and carboxy-terminal portions of MLL are incorporated in a macromolecular complex with histone methyltransferase and histone acetyltransferase function. Functional domains in MLL are indicated in yellow. AT = AT-hooks, a DNA binding domain, CxxC = motif recognizing unmethylated CpG dinucleotides, PHD = plant homeodomain, SET = histone methyltransferase active site. Proteins associated with MLL are explained in the text.
Figure 3.
Figure 3.
Molecular pathways leading to oncogenic activity of MLL fusion proteins. MLL fusions are aberrant transcription factors that activate gene expression. Four different mechanisms have been suggested as to how fusion partners might induce transcriptional activation. (A) The most frequent fusion partners of the ENL and AF4 family are members of the EAP complex that combines histone H3K79 methyltransferase activity catalyzed by DOT1L with transcriptional elongation stimulation by pTEFb (positive transcription elongation factor b, a dimer of CDK9 and a cyclinT) that phosphorylates the C-terminal repeat domain of RNA polymerase II. It is speculated that MLL fusion proteins aberrantly recruit this complex to target chromatin. (B) Active histone acetyltransferases are fused to MLL in the MLL-CBP and MLL-p300 proteins. (C) MLL-EEN indirectly recruits the histone H4R3 arginine methyltransferase through binding of the adaptor SAM68. (D) Dimerization of MLL via coiled-coiled or other dimerization domains supplied by the fusion partner activates target genes by unknown mechanisms.
Figure 4.
Figure 4.
The role of HOX proteins in control of hematopoiesis. HOX transcription factors control hematopoietic differentiation. HOX expression must be terminated for maturation to occur, and therefore ectopic presence will block maturation and cause a population of self-renewing precursor cells to expand.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Stass S, Mirro J, Melvin S, Pui CH, Murphy SB, Williams D. Lineage switch in acute leukemia. Blood. 1984;64:701–6. - PubMed
    1. Mirro J, Kitchingman G, Williams D, Lauzon GJ, Lin CC, Callihan T, et al. Clinical and laboratory characteristics of acute leukemia with the 4;11 translocation. Blood. 1986;67:689–97. - PubMed
    1. Mirro J, Kitchingman GR, Williams DL, Murphy SB, Zipf TF, Stass SA. Mixed lineage leukemia: the implications for hematopoietic differentiation. Blood. 1986;68:597–9. - PubMed
    1. Mirro J, Zipf TF, Pui CH, Kitchingman G, Williams D, Melvin S, et al. Acute mixed lineage leukemia: clinicopathologic correlations and prognostic significance. Blood. 1985;66:1115–23. - PubMed
    1. Morse HG, Heideman R, Hays T, Robinson A. 4;11 translocation in acute lymphoblastic leukemia: a specific syndrome. Cancer Genet Cytogenet. 1982;7:165–72. - PubMed

MeSH terms