Molecular analysis of the t(15;17) translocation in de novo and secondary acute promyelocytic leukemia.
To study mechanism of chromosomal translocation, we analyzed the breakpoints (b/p) of the PML and RARA genes in 120 and 5 patients with de novo and secondary (therapy-related) acute promyelocytic leukemia (APL), respectively. In de novo APL, the b/p in the PML gene were clustered in introns 3 (bcr 3; 30%) and around intron 6 (bcr 1 and 2: 70%). The b/p of the RARA gene were widely distributed in intron 2. In studied 8 de novo APL patients, no consensus sequence-motif was found around the b/p, but there were identical stretches of one to seven nucleotides between the PML and RARA genes in the joining regions, suggesting non-selective DNA double strand cleavage followed by single strand base-pairing within identical short stretches as a molecular mechanism of the translocation. In 4 secondary APL patients after chemotherapy including etoposide against Langerhans cell histiocytosis, the b/p of the PML gene were located in intron 6, and those of the RARA gene were in a restricted region within intron 2, 1 kb EcoRI-BamHI fragment, while in an APL patient after chemotherapy without etoposide against breast cancer, the b/p of the PML and RARA genes were located in intron 6 and another region within intron 2, respectively. These data suggest that a different mechanism was associated with the t(15;17) translocation in etoposide-related APL.
Naoe
T
T
Department of Medicine, Nagoya University Branch Hospital, Japan.
Kudo
K
K
Yoshida
H
H
Horibe
K
K
Ohno
R
R
D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects; D001483:Base Sequence; D015139:Blotting, Southern; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D016384:Consensus Sequence; D005047:Etoposide / Q000009:adverse effects; D006801:Humans; D007438:Introns; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D009363:Neoplasm Proteins; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000235:genetics*; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins
D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D005047:Etoposide