title: A translocation in acute lymphoblastic leukemia that cytogenetically mimics the recurrent MLL-AFF1 translocation and fuses SEPT11 to MLL.
abstract: A 55-year-old man sought care for aggressive acute lymphoblastic leukemia (ALL), which developed 8 years after he had received chemotherapeutic treatment for nephrotic syndrome. The sole cytogenetic abnormality observed in bone marrow-derived metaphases was a t(4;11)(q21;q23), which is a frequently occurring translocation in ALL. However, subsequent reverse transcriptase-polymerase chain reaction for the expected mixed lineage leukemia [trithorax homolog, Drosophila] (MLL)-AFF1 fusion transcript was negative. Further fluorescence in situ hybridization (FISH) analysis narrowed the 4q21 breakpoint down to a 250-kb region proximal of AFF1. This comprised four genes, of which septin11 (SEPT11) was further analyzed. Reverse transcriptase-polymerase chain reaction revealed expression of a chimeric MLL-SEPT11 transcript, thus identifying what is to our knowledge a hitherto undescribed translocation in ALL. Sequence analysis of cDNA showed in-frame fusion of MLL exon 11 to SEPT11 exon 2. This MLL-SEPT11 fusion is cytogenetically indistinguishable from the recurrent t(4;11)(q21;q23). Thus, it is crucial to characterize cytogenetic aberrations in leukemia by molecular methods, even in cases where a known recurrent translocation is presumed. This report expands the spectrum of ALL-related translocations and hypothesizes on the mechanism leading to the MLL-SEPT11 fusion. Five septins have been identified thus far as MLL fusion partners in leukemia. Their putative oncogenic role may be related to forced MLL dimerization by the septin coiled coil and GTP-binding domains, which could convert MLL to an oncogene.
authors.affiliation: Department of Clinical Genetics, Unit of Cytogenetics, Maastricht University Medical Center, Maastricht, the Netherlands. servi.stevens@gen.unimaas.nl
authors.forename: Servi J C
authors.initials: SJ
authors.lastname: Stevens
authors.forename: Laurence E C
authors.initials: LE
authors.lastname: Meers
authors.forename: Jozefa C M
authors.initials: JC
authors.lastname: Albrechts
authors.forename: Karien
authors.initials: K
authors.lastname: Mebis-Verhees
authors.forename: Gerard M J
authors.initials: GM
authors.lastname: Bos
authors.forename: John J M
authors.initials: JJ
authors.lastname: Engelen
authors.forename: Jannie W H
authors.initials: JW
authors.lastname: Janssen
mesh_terms: D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11; D002894:Chromosomes, Human, Pair 4; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D050939:Gene Fusion; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007621:Karyotyping; D008297:Male; D008875:Middle Aged; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058112:Septins; D035602:Transcriptional Elongation Factors; D014178:Translocation, Genetic
chemical_list: D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D011495:Histone-Lysine N-Methyltransferase; C496549:SEPTIN11 protein, human; D058112:Septins