title: Loss of heterozygosity and microsatellite instability at the MLL locus are common in childhood acute leukemia, but not in infant acute leukemia.
abstract: Rearrangements involving the MLL gene at chromosome 11q23 are associated with leukemia and are present in up to 70% of infant leukemias. Loss of heterozygosity (LOH) has been shown for anonymous polymorphic markers at 11q23 in adult leukemias. To study LOH at the MLL locus, we have identified two new polymorphic microsatellite markers: a GAA repeat (mllGAAn) in intron 6 of the MLL gene and a GA (mllGAn) repeat in the 5' flanking region of the gene, approximately 2 kb upstream of the translation initiation codon. The heterozygosity index of mllGAAn is 0.54, which renders it useful for analyzing LOH. We screened two groups of leukemia patients to study LOH at the mllGAAn marker. Group A (n = 18) was selected on the basis of presentation before 18 months. Cytogenetic and reverse transcription-polymerase chain reaction analysis showed that 9 of these 18 children had translocations involving MLL. No LOH was observed. Group B (n = 36) were randomly selected children who had presented with leukemia between 1993 and 1994. Cytogenetic analysis of this group showed a variety of different chromosomal abnormalities. LOH was shown in 9 of 20 individuals (45%) who were informative. Microsatellite instability (MSI) was demonstrated in 1 of 18 individuals in group A and 5 of 36 individuals (13.9%) in group B. MSI and LOH were observed simultaneously in three individuals. Loss of an allele was confirmed in one individual by fluorescence in situ hybridization. Individuals with MSI or LOH at mllGAAn were selected for analysis at anonymous polymorphic markers D11S1364 and D11S1356, which flank the MLL gene. No LOH or MSI was observed at these markers in those individuals who were informative. These results show that LOH at the MLL gene locus is a common event during leukemogenesis. Furthermore, the presence of MSI at this locus suggests that the region is a hotspot for genetic instability.
authors.affiliation: Leukaemia Research Fund, Paul O'Gorman Centre for Childhood Leukaemia, Molecular Haematology Unit, Institute of Child Health, London, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Webb
authors.forename: I
authors.initials: I
authors.lastname: Golovleva
authors.forename: A H
authors.initials: AH
authors.lastname: Simpkins
authors.forename: H
authors.initials: H
authors.lastname: Kempski
authors.forename: B
authors.initials: B
authors.lastname: Reeves
authors.forename: N
authors.initials: N
authors.lastname: Sturt
authors.forename: J M
authors.initials: JM
authors.lastname: Chessells
authors.forename: P M
authors.initials: PM
authors.lastname: Brickell
mesh_terms: D000208:Acute Disease; D000328:Adult; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11; D004276:DNA, Satellite / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000235:genetics* / Q000503:physiopathology; D019656:Loss of Heterozygosity; D051788:Myeloid-Lymphoid Leukemia Protein; D011110:Polymorphism, Genetic; D011519:Proto-Oncogenes; D014157:Transcription Factors
chemical_list: D004276:DNA, Satellite; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase