Microsatellite instability and frameshift mutations in BAX and transforming growth factor-beta RII genes are very uncommon in acute lymphoblastic leukemia in vivo but not in cell lines.
Mutations in the DNA mismatch repair (MMR) system lead to an instability of simple repetitive DNA sequences involved in several cancer types. This instability is reflected in a high mutation rate of microsatellites, and recent studies in colon cancer indicate that defects in MMR result in frequent frameshift mutations in mononucleotide repeats located in the coding regions of BAX and transforming growth factor-beta (TGF-beta) receptor genes. Circumstantial evidence suggests that the MMR defect may be involved in some lymphoid malignancies, although several allelotype analyses have concluded on the low level of microsatellite instability in acute lymphoblastic leukemias. To further evaluate the implication of MMR defects in leukemogenesis, we have studied a series of 98 children with acute lymphoblastic leukemia and 14 leukemic cell lines using several indicators of MMR defects. Microsatellite markers were compared between blast and normal DNA from the same patients and mutations were sought in mononucleotide repeat sequences of BAX and TGF-beta receptor II (TGF-beta RII). The absence of microsatellite instability (MI) and the absence of mutations in the genes examined from patient's leukemic cells contrasted with the observation that half of the cell lines displayed a high degree of MI and that three of seven of these mutator cell lines harbored mutations in BAX and/or TGF-beta RII. From these results we conclude that MMR defects are very uncommon in freshly isolated blasts but are likely to be selected for during the establishment of cell lines.
Molenaar
J J
JJ
INSERM U409, Association Claude Bernard, Faculté de Médecine Xavier Bichat, Paris, France.
Gérard
B
B
Chambon-Pautas
C
C
Cavé
H
H
Duval
M
M
Vilmer
E
E
Grandchamp
B
B
D014408:Biomarkers, Tumor; D004276:DNA, Satellite / Q000235:genetics*; D016368:Frameshift Mutation; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D014408:Biomarkers, Tumor; D004276:DNA, Satellite; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016212:Transforming Growth Factor beta; D051028:bcl-2-Associated X Protein