1999 Fiscal Year Final Research Report Summary
Research on the mechanism of resistance to retinoic aid in acute promyelocytic leukemia
| Project/Area Number |
10670702
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | TOHOKU UNIVERSITY |
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Principal Investigator |
IMAIZUMI Masue School of Medicine, Tohoku University, Associate Professor, 大学院・医学系研究科, 助教授 (40191895)
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Hosiro School of Medicine, Tohoku University, Research Associate, 医学部・附属病院, 助手 (00292334)
IDE Hiroyuki School of Science, Tohoku University, Professor, 大学院・理学研究科, 教授 (70022704)
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| Project Period (FY) |
1998 – 1999
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| Keywords | Acute promyelocytic / retinoic aid / ATRA resistance / PML / RARα / acquired mutatien |
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| Research Abstract |
The binding of all-trans retinoic acid (ATRA) to the ligand-binding region in the E-domain of retinoic acid receptor-alpha modifies the transcriptional activity of RARalpha protein. ATRA probably induces differentiation of acute promyelocytic leukemia (APL) cells by binding to the E-domain of the RARalpha portion (RARalpha/E-domain) of PML/RARalpha chimeric protein. Therefore, molecular alteration in the RARalpha/E-domain of the chimeric gene is one mechanism by which patients with APL may acquire resistance to ATRA therapy. In this study reverse transcription-polymerase chain reaction and single-strand conformation polymorphism, DNA segments amplified from the RARalpha/E-domain in fresh APL cells of 23 APL patients (8 males and 15 females from 4 to 76 years of age) were screened for mutations. OF those patients, 3 patients (1 with de novo and 2 with relapse) had clinical resistance to ATRA therapy. We found mutations in the RARalpha/E-domain of PML/RARalpha chimeric gene exclusively in the 2 patients who exhibited ATRA-resistance at relapse, whereas the mutations were not detected at their initial onset. Interestingly, these patients received a prolonged or intermittent administration of ATRA before relapse with ATRA-resistance. The mutations lead to the change of amino acid in the ligand-binding region of RARalpha/E-domain, Arg272Gln, or Met297Leu according to the amino acid sequence of RARalpha, respectively. Further study that the in vitro ligand-dependent transcriptional activity of the mutant PML/RARalpha protein was significantly decreased as compared with that of wild-type PML/RARalpha. These findings suggest that mutations in the RARalpha/E-domain of the PML/RARalpha chimeric gene may confer clinical resistance to ATRA therapy in patients with APL.
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