MLL-SEPTIN6 fusion recurs in novel translocation of chromosomes 3, X, and 11 in infant acute myelomonocytic leukaemia and in t(X;11) in infant acute myeloid leukaemia, and MLL genomic breakpoint in complex MLL-SEPTIN6 rearrangement is a DNA topoisomerase II cleavage site

Abstract

We examined the MLL translocation in two cases of infant AML with X chromosome disruption. The Gbanded karyotype in the first case suggested t(X;3)(q22;p21)ins(X;11)(q22;q13q25). Southern blot analysis showed one MLL rearrangement. Panhandle PCR approaches were used to identify the MLL fusion transcript and MLL genomic breakpoint junction. SEPTIN6 from chromosome band Xq24 was the partner gene of MLL. MLL exon 7 was joined in-frame to SEPTIN6 exon 2 in the fusion transcript. The MLL genomic breakpoint was in intron 7; the SEPTIN6 genomic breakpoint was in intron 1. Spectral karyotyping revealed a complex rearrangement disrupting band 11q23. FISH with a probe for MLL confirmed MLL involvement and showed that the MLL-SEPTIN6 junction was on the der(X). The MLL genomic breakpoint was a functional DNA topoisomerase II cleavage site in an in vitro assay. In the second case, the karyotype revealed t(X;11)(q22;q23). Southern blot analysis showed two MLL rearrangements. cDNA panhandle PCR detected a transcript fusing MLL exon 8 in-frame to SEPTIN6 exon 2. MLL and SEPTIN6 are vulnerable to damage to form recurrent translocations in infant AML. Identification of SEPTIN6 and the SEPTIN family members hCDCrel and MSF as partner genes of MLL suggests a common pathway to leukaemogenesis.

DNA topoisomerase II, genotoxicity, and cancer

“…Even though genistein and other bioflavonoids appear to be chemopreventative in adults, the maternal consumption (during pregnancy) of foods that are naturally high in these topoisomerase II poisons increases the risk of developing these infant leukemias more than 3-fold [148]. Once again, chromosomal breakpoints in these leukemias are proximal to topoisomerase II cleavage sites [149].…”

The MYO1F, unconventional myosin type 1F, gene is fused to MLL in infant acute monocytic leukemia with a complex translocation involving chromosomes 7, 11, 19 and 22

“…Particularly, these translocations were frequently observed in t(10;11)(p12;q23) creating MLL-AF10 (Beverloo et al, 1995;Shibuya et al, 2001) and t(X;11)(q22-24;q23) creating MLL-SEPT6 (Ono et al, 2002a;Slater et al, 2002), because the direction of transcription of AF10 and SEPT6 is opposite to that of MLL. Therefore in t(10;11)(p12;q23) or t(X;11)(q22-24;q23), an inversion of a part of chromosome including MLL, AF10 or SEPT6 inserts adjacent to the partner gene to form regular head-to-tail fusion transcripts (Beverloo et al, 1995;Fu et al, 2003).…”

Cleavage of the MLL gene by activators of apoptosis is independent of topoisomerase II activity

“…14 Substantial data have been generated, however, showing a correlation between the site of in vitro topoisomerase II cleavage and the location of breakpoint fusion junctions. [15][16][17] An alternative mechanism that has been discussed, perhaps best termed the 'apoptotic nuclease' model, proposes that it is the activation of an apoptotic nuclease that initiates cleavage within MLL. 8,10 Here, using an in vitro system, translocations could be generated by exposure to activators of apoptosis with no known link to topoisomerase II.…”