2000 Fiscal Year Final Research Report Summary
Molecular mechanisms and in vivo models for retinoid resistance in leukemic cells
| Project/Area Number |
11671016
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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 |
Hematology
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| Research Institution | Keio University |
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Principal Investigator |
TAKAYAMA Nobuyuki Keio University School of Medicine, Instructor, 医学部, 助手 (50206893)
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| Co-Investigator(Kenkyū-buntansha) |
IKEDA Yasuo Keio University School of Medicine, Professor, 医学部, 教授 (00110883)
KIZAKI Masahiro Keio University School of Medicine, Assistant Professor, 医学部, 講師 (20161432)
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| Project Period (FY) |
1999 – 2000
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| Keywords | acute promyelocytic leukemia / all-trans retinoic acid (ATRA) / ATRA resistance / PML-RARα / co-repressor |
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| Research Abstract |
Acute promyelocytic leukemia (APL) is characterized by specific chromosomal translocation t(15 ; 17), which generates PML/RARα chimeric gene. All-trans retinoic acid (ATRA) is a highly effective agent against APL patients by inducing differentiation of leukemia cells. Although ATRA is very active against untreated APL, prolonged administration of ATRA invariably results in ATRA resistance, which is now becoming a serious clinical problem.
We have previously established a novel APL cell line, UF-1, from a patient who was resistant to ATRA therapy (Kizaki et al, Blood, 88 : 1824, 1996). UF-1 cells show stable feature of ATRA resistance in in vitro culture, indicating this cell line is an excellent model for clinical ATRA resistance. We examined nucleotide sequences of PML/RARα gene in UF-1 cells and detected a point mutation in the ATRA-binding domain in RARα portion of this chimeric gene [Arg^<611> (CGG)→Trp^<611> (TGG)]. Transfection assay showed that mutant PML/RARα protein exhibits dramatically decreased ATRA-binding activity. The same mutation was detected in preserved clinical sample of the original patient.
These resuls show that the molecular mechanism of clinical ATRA resistance is explained at least in part by the structural alteration of PML/RARα gene.
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