title: 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 G-banded 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.
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, PA 19104, USA.
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Slater
authors.forename: Eva
authors.initials: E
authors.lastname: Hilgenfeld
authors.forename: Eric F
authors.initials: EF
authors.lastname: Rappaport
authors.forename: Narayan
authors.initials: N
authors.lastname: Shah
authors.forename: Rita G
authors.initials: RG
authors.lastname: Meek
authors.forename: Wendy Reed
authors.initials: WR
authors.lastname: Williams
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lovett
authors.forename: Neil
authors.initials: N
authors.lastname: Osheroff
authors.forename: Reshma S
authors.initials: RS
authors.lastname: Autar
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Felix
mesh_terms: D000208:Acute Disease; D001483:Base Sequence; D019457:Chromosome Breakage / Q000235:genetics; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D003598:Cytoskeletal Proteins; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007951:Leukemia, Myeloid / Q000235:genetics*; D015479:Leukemia, Myelomonocytic, Acute / Q000235:genetics; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein; D011519:Proto-Oncogenes; D058112:Septins; D014157:Transcription Factors; D014178:Translocation, Genetic / Q000235:genetics*; D014960:X Chromosome / Q000235:genetics*
chemical_list: D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D019204:GTP-Binding Proteins; C436485:SEPTIN6 protein, human; D058112:Septins; D004250:DNA Topoisomerases, Type II