MLL-r fusion transcripts in healthy individuals by induced gene proximity

Chromosomal rearrangements are a major cause of hemato-malignant diseases. With about 10% of the ALL and 5% of the AML cases, MLL-rearrangements play a key role for the onset of leukemia. The specific chromosomal translocation t(4;11) has been identified in 50% of infant ALL, 44% of pediatric ALL and 80% of adult ALL cases. Here, we asked the question why the AF4 gene is such a prominent fusion partner in MLL-r leukemia. Different investigations have already shown that chimeric fusion RNAs are produced in white blood cells of healthy donors (e.g. BCR-ABL, MLL-AF4). We have shown recently that these fusion transcripts are formed by trans-splicing events which may be caused by "early terminated transcripts". Now we present the formal prove that an experimental induction of "gene proximity" in the interphase nucleus is sufficient to allow the formation of MLL-AF4 fusion transcripts in the absence of any t(4;11) translocation (missing AF4-MLL fusion transcript). Thus, "gene proximity" in combination with certain "transcriptional features" (termination of primary transcripts in the bcr of genes) are likely to be the cause for the onset of chromosomal translocations.

Publication History

Article published online:
17 May 2022