Distinct mechanisms lead to HPRT gene mutations in leukemic cells.
Leukemias are considered malignant clonal disorders arising from the accumulation of mutations in hematopoietic cells; the majority of these mutations are thought to be acquired somatically. Measurement of mutation frequency (Mf) at the hypoxanthine phosphoribosyltransferase (HPRT) locus has been developed as a method for estimating genomic instability. We investigated the Mf in 16 leukemic cell lines to determine whether these cell lines showed evidence of genomic instability. Although some leukemic cell lines had markedly elevated Mfs, the Mfs at the HPRT locus in leukemic cell lines were not always higher than those of B-lymphoblastoid cell lines and T lymphocytes from normal individuals. We were able to identify the HPRT mutation for 159 of 160 individual HPRT mutants. The HPRT mutations were characterized at a molecular level and classified as either gross chromosomal rearrangements (GCRs) or point mutations, such as single-nucleotide substitutions, insertions, or deletions. With rare exceptions, individual leukemic cell lines showed either point mutations or GCR, but not both. Of note, all the cell lines that primarily showed point mutations are known to be defective in mismatch repair machinery.
Lin
Ying-Wei
YW
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20889-510, USA. aplanp@mail.nih.gov
Perkins
Jonathan J
JJ
Zhang
Zhenhua
Z
Aplan
Peter D
PD
D000293:Adolescent; D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics; D018922:HL-60 Cells / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D019169:Jurkat Cells / Q000737:chemistry / Q000378:metabolism; D020014:K562 Cells / Q000737:chemistry / Q000378:metabolism; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D008297:Male; D016296:Mutagenesis / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010865:Pilot Projects; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics; D020298:U937 Cells / Q000737:chemistry / Q000378:metabolism
D005819:Genetic Markers; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D007041:Hypoxanthine Phosphoribosyltransferase