Introduction

MLL

MLL (mixed-lineage leukemia) is a large gene that spans approximately 88 kb of DNA and contains 36 exons (see GcbCisregulatoryregions). It encodes a 431-kD protein of more than 3,910 amino acids, containing 3 regions with homology to sequences within the Drosophila 'trithorax' gene, including cysteine-richregions that can be folded into 6 zinc finger-like domains. The MLL protein has DNA methyltransferase domain and a SET domain, which is a histone H3 lys4 (K4)-specific methyltransferase. This histone methylase activity was found to be associated with HOX gene activation and H3 K4 methylation at cis regulatory sequences in vivo. MLL is present within a stable multiprotein supercomplex composed of at least 29 proteins. The majority of the complex proteins are components of transcription complexes, including TFIID. Other components are involved in RNA processing or histone methylation. The complex remodels, acetylates, deacetylates, and methylates nucleosomes and/or free histones. MLL is cleaved by the protease taspase-1 at 2c onserved sites to generate an N-terminal 320-kD fragment (N320) and a C-terminal 180-kD fragment (C180), which heterodimerize to stabilize the complex and confer its subnuclear destination.

Source (Entrez Gene) (OMIM)

MLL in disease

Recurring chromosomal translocations involving chromosome 11, band q23, have been observed in acute lymphoid leukemias and especially in acute myeloid leukemias (AML). The breakpoints in four 11q23 translocations associated with leukemia were contained within a yeast artificial chromosome (YAC) clone bearing the Cd3d and Cd3g gene loci. Within this YAC, a transcription unit that spans the breakpoint junctions of 3 of these translocations, 4;11, 9;11, and 11;19 was identified. 2 other related transcripts were described, that were upregulated in a translocation cell line. This gene was named MLL for myeloid/lymphoid, or mixed lineage, leukemia. The breakpoint cluster region within MLL spans 8 kb and encompasses several small exons, most of which begin in the same phase of the open reading frame. The types of acute lymphoblastic leukemia and acute myeloid leukemia that are particularly associated with translocations involving 11q23 are acute monoblastic leukemia(AML-M5) and acute myelomonocytic leukemia (AMML-M4).

The MLL gene spans the breakpoint in translocations involving 11q23 which are responsible for approximately 70% of AML and ALL in infants and are also observed in treatment-related leukemias, especially in patients previously treated with drugs inhibiting topoisomerase II. Unique or clonotypic MLL-AF4 genomic fusion sequences were detectable in neonatal blood spots from individuals who developed ALL at ages 5 months to 2 years, thus providing unequivocal evidence for a prenatal initiation of acute leukemia in young patients. Common subtypes due to other translocation fusion genes can be expected to have a similar prenatal initiation. Epidemiologic studies suggested that maternal exposure to various substances such as pesticides, marijuana, or an excess of flavonoids (naturally occurring inhibitors of topoisomerase II) might be associated with acute leukemia in infants. Clustering algorithms showed that lymphoblastic leukemias with MLL translocations can clearly be separated from conventional acute lymphoblastic and acute myelogenous leukemias. They proposed that they constitute a distinct disease, denoted as MLL, and showed that the differences in gene expression are robust enough to classify leukemias correctly as MLL versus acute lymphoblastic leukemia or acute myelogenous leukemia.

Translocations involving 11q23 in leukemia resultin the translocation of zinc finger domains with fusion to other genes on chromosome 4, chromosome 9, or chromosome 19. The gene on chromosome 19 with which it is fused is ENL. The genes with which it is fused on chromosome 4 (AF4) and chromosome 9 (AF9) show high homology of sequence to ENL. The protein products of the AF4, AF9, and ENL proteins contained nuclear targeting sequences as well as serine-rich and proline-rich regions. Many genes that can fuse with MLL, including AF6, AF9, FBP17, LPP, PNUTL1 and gephyrin, among others. The MLL gene is leukemogenic when it fuses with itself as well as when it fuses with one of the genes on other chromosomes. A direct tandem duplication involved a region spanning exons 2 to 6, and a partially duplicated protein gene product was demonstrated.

Source (OMIM)

Animal Models of MLL

Yu et al. (1995)

• Mll deletion in mice was embryonic lethal.
• Mll+/- mice had retarded growth, hemopoietic abnormalities and bidirectional homeotic transformation of the axial skeleton (with altered Hox gene expression), as well as sternal malformations.

Yamashita et al. (2006)

• Role of MLL in the immune system using Mll +/- mice:
  • Mll+/- Cd4-positive T cells differentiated normally into antigen-specific effector Th1 and Th2 cells in vitro, but the ability of memory Th2 cells to produce Th2 cytokines was dramatically decreased.
  • Histone methylation and acetylation at Th2 cytokine gene loci was not maintained in Mll+/- memory Th2 cells. Levels of Gata3 mRNA were normal in Mll +/- effector Th2 cells, but they were substantially decreased in Mll +/- memory Th2 cells; mRNA levels of other transcription factors were not affected in Mll +/- memory Th2cells. Histone modifications of Gata3 were also aberrant in Th2 cell lines in which Mll expression had been knocked down by small interfering RNA.
  • Ovalbumin-induced allergic eosinophilic inflammation was reduced in Mll +/- Th2 cell-transferred mice.

Barabe et al. (2007)

• Upon transplantation into immunodeficient mice, primitive human hematopoietic cells expressing a mixed-lineage leukemia (MLL) fusion gene generated myeloid or lymphoid acute leukemias, with features that recapitulated human diseases.

McMahon et al. (2007)

• Fetal liver from MLL-knockout mouse embryos showed defects in the hematopoietic stem and progenitor pool, including reductions in long-term and short-term hematopoietic stem cell numbers and a decrease in the quiescent hematopoietic stem cell fraction.

• Adult mice with conditional Mll knockout had no apparent abnormalities in mature hematopoietic cells in bone marrow, spleen, and thymus. However, conditional Mll-knockout bone marrow cells produced reduced numbers of colony-forming units and showed reduced ability to compete in hematopoietic reconstitution assays.

Source (OMIM)