MLL: How complex does it get?

Abstract

The mixed lineage leukemia (MLL) gene encodes a very large nuclear protein homologous to Drosophila trithorax (trx). MLL is required for the proper maintenance of HOX gene expression during development and hematopoiesis. The exact regulatory mechanism of HOX gene expression by MLL is poorly understood, but it is believed that MLL functions at the level of chromatin organization. MLL was identified as a common target of chromosomal translocations associated with human acute leukemias. About 50 different MLL fusion partners have been isolated to date, and while similarities exist between groups of partners, there exists no unifying property shared by all the partners. MLL gene rearrangements are found in leukemias with both lymphoid and myeloid phenotypes and are often associated with infant and secondary leukemias. The immature phenotype of the leukemic blasts suggests an important role for MLL in the early stages of hematopoietic development. Mll homozygous mutant mice are embryonic lethal and exibit deficiencies in yolk sac hematopoiesis. Recently, two different MLL-containing protein complexes have been isolated. These and other gain-and loss-of-function experiments have provided insight into normal MLL function and altered functions of MLL fusion proteins. This article reviews the progress made toward understanding the function of the wild-type MLL protein. While many advances in understanding this multifaceted protein have been made since its discovery, many challenging questions remain to be answered. J. Cell. Biochem. 95: 234-242, 2005. ß 2005 Wiley-Liss, Inc.

Aberrant overexpression and function of the miR-17-92 cluster in MLL -rearranged acute leukemia

“…Indeed, MLL belongs to the Trithorax Group (trx-G) of proteins, which antagonizes the repressive function of the Polycomb Group (Pc-G) proteins and positively regulates gene expression through chromatin association and modification. The best studied downstream targets of MLL and trx function are the homeobox (HOX) genes such as HOXA9, as well as the HOX cofactor MEIS1 (25). MLL is believed to function at the level of chromatin organization through its C-terminal SET domain that possesses intrinsic histone methytransferase activity specific for H3K4; trimethylation of H3K4 is a long-lasting marker associated with an active gene (38).…”

“…MLL-rearranged leukemia is classified as a disease of poor prognosis (19,20), and cure rates for ALL patients with MLL rearrangements remain dismal (typically ≈20% and only one-third of AML patients with MLL rearrangements will survive longer than 5 years) (21). More than 60 different loci have been identified to translocate to the MLL gene locus (22)(23)(24)(25). The critical feature of these chromosomal rearrangements is the generation of a chimeric transcript consisting of 5′ MLL and 3′ sequences of the gene on the partner chromosome.…”

Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay

“…Alternatively, a regional breakdown in activating factors that maintain active chromatin domains at homeobox genes, such as MLL1, a member of the mammalian trithorax group, and H3K4 methyltransferase, may ultimately lead to a shift in histone modification patterns and de novo methylation in cancer cells (50)(51)(52). A complete understanding of the range and patterns of CpG island methylation within tumors and premalignant lesions will be an important step toward understanding of the mechanistic pathways leading to hypermethylation of genes during tumorigenesis.…”

Epigenetic regulations in hematopoietic Hox code

“…The Mll gene is frequently targeted by chromosomal translocations in acute lymphoid and myeloid leukemias (ALL and AML, respectively) (Ayton and Cleary, 2001). There are various MLL fusion proteins with the N-terminal portion of MLL fused in frame with 1 of over 60 different potential fusion partners (Hess, 2004;Popovic and Zeleznik-Le, 2005). Both human and murine leukemias triggered by MLL-AF9 are most frequently myeloid in phenotype (Sorensen et al, 1994;Look, 1997;Dobson et al, 1999).…”