Chromosomal rearrangements leading to MLL gene fusions: clinical and biological aspects

Abstract

Rearrangements of the MLL gene located at 11q23 are common chromosomal abnormalities associated with acute leukemia, especially infant and therapy-related leukemias. A variety of chimeric oncoproteins resulting from these rearrangements has been described; all of these include the NH(2)-terminal region of MLL implicated in protein-protein interactions and transcriptional repression. Although the molecular basis for the oncogenic activity of MLL chimeric proteins is incompletely understood, it seems to be derived, at least in part, through activation of clustered homeobox (HOX) genes. Here, we survey MLL gene rearrangements that are associated with acute leukemia and discuss molecular pathways leading to these rearrangements.

Figure 1. Structure of the MLL gene and protein

(a) Schematic representation of MLL gene showing location of the PTD (partial tandem duplication, see text) and BCR (breakpoint cluster region, which encompasses almost all known MLL translocation breakpoints). Exon size and intronic distances are not to scale. (b) Location of MLL protein domains in relation to BCR, PTD, and fusion partners. AT-hook [DNA binding motif that binds adenosine-thymidine (AT) rich DNA], SNL (speckled nuclear localization sites), DNMT (DNA methyltransferase domain), PHD (plant homeodomains), TAD (transactivation domain), SET [SET (for Suppressor of variegation/Enhancer of zeste/Trithorax) domain]. Cleavage by Taspase (Threonine-aspartase) 1 divides MLL in N- and C-terminal fragments.