title: Diagnostic tool for the identification of MLL rearrangements including unknown partner genes.
abstract: Approximately 50 different chromosomal translocations of the human MLL gene are currently known and associated with high-risk acute leukemia. The large number of different MLL translocation partner genes makes a precise diagnosis a demanding task. After their cytogenetic identification, only the most common MLL translocations are investigated by RT-PCR analyses, whereas infrequent or unknown MLL translocations are excluded from further analyses. Therefore, we aimed at establishing a method that enables the detection of any MLL rearrangement by using genomic DNA isolated from patient biopsy material. This goal was achieved by establishing a universal long-distance inverse-PCR approach that allows the identification of any kind of MLL rearrangement if located within the breakpoint cluster region. This method was applied to biopsy material derived from 40 leukemia patients known to carry MLL abnormalities. Thirty-six patients carried known MLL fusions (34 with der(11) and 2 with reciprocal alleles), whereas 3 patients were found to carry novel MLL fusions to ACACA, SELB, and SMAP1, respectively. One patient carried a genomic fusion between MLL and TIRAP, resulting from an interstitial deletion. Because of this interstitial deletion, portions of the MLL and TIRAP genes were deleted, together with 123 genes located within the 13-Mbp interval between both chromosomal loci. Therefore, this previously undescribed diagnostic tool has been proven successful for analyzing any MLL rearrangement including previously unrecognized partner genes. Furthermore, the determined patient-specific fusion sequences are useful for minimal residual disease monitoring of MLL associated acute leukemias.
authors.affiliation: Institute of Pharmaceutical Biology/Center for Drug Research, Development and Safety (ZAFES), Biocenter, University of Frankfurt, D-60439 Frankfurt/Main, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Meyer
authors.forename: Bjoern
authors.initials: B
authors.lastname: Schneider
authors.forename: Martin
authors.initials: M
authors.lastname: Reichel
authors.forename: Sieglinde
authors.initials: S
authors.lastname: Angermueller
authors.forename: Sabine
authors.initials: S
authors.lastname: Strehl
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Claudia
authors.initials: C
authors.lastname: Schoch
authors.forename: Mieke W J C
authors.initials: MW
authors.lastname: Jansen
authors.forename: Jacques J
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: Oskar A
authors.initials: OA
authors.lastname: Haas
authors.forename: Theo
authors.initials: T
authors.lastname: Dingermann
authors.forename: Thomas
authors.initials: T
authors.lastname: Klingebiel
authors.forename: Rolf
authors.initials: R
authors.lastname: Marschalek
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics*; D020690:GTPase-Activating Proteins; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051788:Myeloid-Lymphoid Leukemia Protein; D011519:Proto-Oncogenes / Q000235:genetics*; D017472:Receptors, Interleukin-1 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; C497422:KMT2A protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D017472:Receptors, Interleukin-1; C107022:SMAP1 protein, human; C434984:TIRAP protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase