Extending the repertoire of the mixed-lineage leukemia gene MLL in leukemogenesis

  1. Angelika Daser and
  2. Terence H. Rabbitts1
  1. MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, UK

This extract was created in the absence of an abstract.

Chromosomal1 translocations are key elements in tumor etiology, as these somatically created abnormal chromosomes have activated oncogenes where the chromosome breakpoints occur (for review, see Rabbitts 1994). Most often, gene fusions are caused by chromosomal translocations, which frequently break within the exons of the two involved chromosomes, allowing the transcription product to encompass the linked exons, for post-transcriptional processing to splice these exons to create a tumor-specific fusion mRNA and in turn fusion protein. This type of event is common in both leukemias and in sarcomas (Rabbitts 1994; Look 1997). The leukemias divide into chronic and acute forms of cancer. The translocation genes involved can be roughly categorized into distinct types, with those involved in acute leukemia often being transcription regulators (Cleary 1991) whose role as master genes in cell fate determination is a key element in their role in leukemias (Rabbitts 1991). Thus, activated oncogenes or gene fusions influence differentiation in cell-specific ways and the tropism of specific chromosomal translocations for specific cell types is a manifestation of this role.

The ubiquitous MLL gene and its multitude of chromosomal abnormalities

Among the most common chromosomal breakpoint regions in human leukemias is the long arm (q) of chromosome 11 at band q23 (Rowley 1993, 1998; Look 1997; Ayton and Cleary 2001). A gene called the mixed-lineage leukemia gene, MLL (or HTRX, HRX, TRX1, ALL-1; Ziemin-van der Poel et al. 1991; Djabali et al. 1992; Gu et al. 1992; Tkachuk et al. 1992; Domer et al. 1993), is found at the breakpoints of the many and disparate chromosomal translocations of 11q23 (as well as cases of internal duplication of 11q23, often associated with trisomy 11; Schichman et al. 1994, 1995; Caligiuri et al. 1996; Schnittger et al. 2000). Chromosomal breakpoints are found in a consistent region of MLL …

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