Possible evidence for acquired genetic activity at both chromosomal breakpoints of the Philadelphia translocation in chronic myeloid leukemia.
The Philadelphia (Ph1) chromosome (22q-), found in more than 90% of patients with chronic myeloid leukemia (CML), is one part of a reciprocal translocation, t(9;22) (q34;q11), in which the oncogene c-abl moves from 9q34 to 22q11. The translocation results in the translation of an aberrant abl-related protein with tyrosine kinase activity. Genetically active genes are known to have chromatin which is hypersensitive to deoxyribonuclease I (DNase I) and to be hypomethylated. Using an in situ nick translation technique on metaphase chromosomes, we have examined DNase I sensitivity and methylation status at the breakpoints 9q34 and 22q11 in bone marrow cells from controls (two cases) and CML patients (three cases). In CML cells DNase I sensitivity was significantly increased, at both breakpoints, in the translocated chromosomes compared with their normal homologues in CML cells and with both homologues in control marrows. A hypermethylated site, seen at 22q11 in normal 22s was hypomethylated on 22q-. The 9q34 region was hypomethylated in normal and translocated chromosomes. DNase I sensitivity, seen at 22q13 in CML cells, was lost following translocation in one of three cases. This technique demonstrates alterations in chromatin conformation and methylation status at translocation breakpoints which may be related to acquired genetic activity at one or both of these sites.
Yamada
T
T
Department of Haematology, Royal Free Hospital School of Medicine, London, UK.
Secker-Walker
L M
LM
D001853:Bone Marrow / Q000473:pathology; D002843:Chromatin / Q000378:metabolism; D002873:Chromosome Fragility; D002892:Chromosomes, Human, Pair 22; D002899:Chromosomes, Human, Pair 9; D002908:Chronic Disease; D003850:Deoxyribonuclease I / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008677:Metaphase; D008745:Methylation; D008875:Middle Aged; D009857:Oncogenes; D010677:Philadelphia Chromosome; D014178:Translocation, Genetic
D002843:Chromatin; D003850:Deoxyribonuclease I