title: Cryptic t(4;11) encoding MLL-AF4 due to insertion of 5' MLL sequences in chromosome 4.
abstract: The t(4;11) translocation is the cytogenetic hallmark of a subset of acute lymphoblastic leukemias characterized by pro-B immunophenotype and a dismal prognosis. This translocation fuses the MLL gene on chromosome band 11q23 and the AF4 gene on 4q21, resulting in the expression of fusion transcripts from both translocated chromosomes. The MLL-AF4 chimeric transcript is thought to mediate the leukemic transformation. The MLL genomic disruption detected by Southern blot and the RT-PCR for the MLL-AF4 chimeric transcript expression are molecular evidence of this chromosomal translocation. However, similar molecular rearrangements have also been identified in cases without the cytogenetic t(4;11). We report a 30-year-old patient with high risk ALL, a normal karyotype, and molecular evidence of MLL-AF4 fusion. Using a double color FISH assay with MLL specific PAC probes, a cryptic t(4;11) due to insertion of 5' MLL sequences in chromosome 4q21 was demonstrated. Consequently the MLL-AF4 was encoded by der(4). This insertion mechanism precludes the genomic recombination of AF4-MLL and supports the crucial role played by MLL-AF4 in leukemogenesis. The findings of our case, along with others, show the importance of complementing the karyotype with molecular and FISH techniques.
authors.affiliation: Department of Pathology, Leiden University Medical Center, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: von Bergh
authors.forename: P
authors.initials: P
authors.lastname: Gargallo
authors.forename: B
authors.initials: B
authors.lastname: De Prijck
authors.forename: H
authors.initials: H
authors.lastname: Vranckx
authors.forename: R
authors.initials: R
authors.lastname: Marschalek
authors.forename: I
authors.initials: I
authors.lastname: Larripa
authors.forename: P
authors.initials: P
authors.lastname: Kluin
authors.forename: E
authors.initials: E
authors.lastname: Schuuring
authors.forename: A
authors.initials: A
authors.lastname: Hagemeijer
mesh_terms: D000328:Adult; D002880:Chromosomes, Human, Pair 11; D002894:Chromosomes, Human, Pair 4; D004268:DNA-Binding Proteins / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051788:Myeloid-Lymphoid Leukemia Protein; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011519:Proto-Oncogenes; D014157:Transcription Factors; D014178:Translocation, Genetic
chemical_list: D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; C113855:MLL-AF4 fusion protein, human; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase