Sequence comparison of putative regulatory DNA of the 5' flanking region of the myeloperoxidase gene in normal and leukemic bone marrow cells.
Myeloperoxidase (MPO) is an enzyme which is exclusively expressed in immature myeloid cells with downregulation of gene expression occurring during granulocytic maturation. Levels of MPO RNA, protein, and enzyme activity differ, usually in a concordant fashion, among the various classes of acute leukemia and among different cases within a particular class. One portion of the gene thought to be involved in regulation of MPO expression is the proximal 5' flanking region. To determine if mutations in this putatively regulatory region of the MPO gene might be responsible for some of the differences in level of MPO expression among different cases or classes of acute leukemia, we compared the nucleotide sequence of this part of the gene from 16 patients with acute leukemia, with DNA from normal human bone marrow cells and selected other neoplasms and cell lines. The sequence of this regulatory region was found to be identical in cases of acute myeloid leukemia (AML) with tha of normal DNA except for a dA to dG transition in the Alu region, 463 bases upstream from the transcription start site. This base substitution was seen in almost all cases of AML studied, regardless of the level of MPO which they expressed. It was absent from normal human DNA obtained from various tissues, and cases of acute and chronic lymphocytic leukemia, carcinoma of lung, and most cell lines examined. The base substitution was also absent in a remission blood sample from one of the cases which showed the dA to dG transition in leukemic marrow, suggesting that the base substitution is a mutation rather than a polymorphism. Our results suggest that mutations in promoter or enhancer DNA are not an important cause of the differences in level of MPO gene expression seen among different cases or different classes of AML. However, the base substitution we have detected could potentially serve as a useful marker for detection of residual disease in patients with AML following treatment.
Pathology and Laboratory Medicine Service (113), Atlanta VA Medical Center, Decatur, GA 30033.
G E
GE
Austin
L
L
Lam
S R
SR
Zaki
W C
WC
Chan
T
T
Hodge
J
J
Hou
D
D
Swan
W
W
Zhang
M
M
Racine
C
C
Whitsett
D001483:Base Sequence; D001853:Bone Marrow / Q000473:pathology*; D001854:Bone Marrow Cells; D004273:DNA, Neoplasm / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D009195:Peroxidase / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid
D004273:DNA, Neoplasm; D009195:Peroxidase