Article

Molecular dissection of t(11;17) in acute myeloid leukemia reveals a variety of gene fusions with heterogeneous fusion transcripts and multiple splice variants.

CCRI, Children's Cancer Research Institute, Kinderspitalgasse 6, Vienna, Austria.
Genes Chromosomes and Cancer (impact factor: 3.31). 12/2006; 45(11):1041-9. DOI:10.1002/gcc.20372 pp.1041-9
Source: PubMed

ABSTRACT The majority of translocations that involve the long arms of chromosomes 11 and 17 in acute myeloid leukemia appear identical on the cytogenetic level. Nevertheless, they are diverse on the molecular level. At present, two genes are known in 11q23 and four in 17q12-25 that generate five distinct fusion genes: MLL-MLLT6/AF17, MLL-LASP1, MLL-ACACA or MLL-SEPT9/MSF, and ZBTB16/PLZF-RARA. We analyzed 14 cases with a t(11;17) by fluorescence in situ hybridization and molecular genetic techniques and determined the molecular characteristics of their fusion genes. We identified six different gene fusions that comprised seven cases with a MLL-MLLT6/AF17, three with a MLL-SEPT9/MSF, and one each with MLL-LASP1, MLL-ACACA, and ZBTB16/PLZF-RARA fusions. In the remaining case, a MLL-SEPT6/Xq24 fusion suggested a complex rearrangement. The MLL-MLLT6/AF17 transcripts were extremely heterogeneous and the detection of seven different in-frame transcript and splice variants enabled us to predict the protein domains relevant for leukemogenesis. The putative MLL-MLLT6 consensus chimeric protein consists of the AT-hook DNA-binding, the methyltransferase, and the CXXC zinc-finger domains of MLL and the highly conserved octapeptide and the leucine-zipper dimerization motifs of MLLT6. The MLL-SEPT9 transcripts showed a similar high degree of variability. These analyses prove that the diverse types of t(11;17)-associated fusion genes can be reliably identified and delineated with a proper combination of cytogenetic and molecular genetic techniques. The heterogeneity of transcripts encountered in cases with MLL-MLLT6/AF17 and MLL-SEPT9/MSF fusions clearly demonstrates that thorough attention has to be paid to the appropriate selection of primers to cover all these hitherto unrecognized fusion variants.

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    Article: Zelluläre, histologische und statistische Untersuchungen zur Funktion des Proteins LASP-1 in humanen Ovar- und Mammakarzinomen
    Thomas Georg Philipp Grünewald
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Keywords

acute myeloid leukemia
 
chromosomes 11
 
cytogenetic level
 
different gene fusions
 
fusion genes
 
generate five distinct fusion genes
 
leucine-zipper dimerization motifs
 
MLL-ACACA
 
MLL-MLLT6/AF17 transcripts
 
MLL-SEPT6/Xq24 fusion
 
MLL-SEPT9 transcripts
 
MLL-SEPT9/MSF
 
MLL-SEPT9/MSF fusions
 
molecular characteristics
 
molecular genetic techniques
 
molecular level
 
protein domains relevant
 
putative MLL-MLLT6 consensus chimeric protein
 
thorough attention
 
ZBTB16/PLZF-RARA fusions