2002 Fiscal Year Final Research Report Summary
Study on mechanism of ATRA-resistance and utility of MRD-monitoring in acute promyelocytic leukemia
| Project/Area Number |
12470163
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 Department of Pediatrics Associate Professor, 大学院・医学系研究科, 助教授 (40191895)
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| Co-Investigator(Kenkyū-buntansha) |
TSURUSAWA Masahito Aichi Medical University, Department of Pediatrics Professor, 教授 (90172064)
TSUCHIYA Shigeru Department of Pediatric Oncology Professor, 加齢医学研究所, 教授 (30124605)
IDE Hiroyuki Department of Biological Institute Professor, 大学院・理学研究科, 教授 (70022704)
HORIBE Keizo National Nagoya Hospital, Department of Pediatrics Associate Professor, 大学院・医学系研究科, 助教授 (30209308)
TSUKIMOTO Ichiro Toho University, Department of Pediatrics Professor, 医学部, 教授 (70100964)
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| Project Period (FY) |
2000 – 2002
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| Keywords | Acute promyelocytic leukemia / all-trans retinoic acid / PML / RARa / mutant PML-RARa / ATRA-resistance / minimal residual disease / MRD monitoring |
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| Research Abstract |
Study on MRD monitoring; In this report MRD monitoring in APL was studied by the differential detection of the PML/RARa gene using standard and nested RT-PCR. The sensitivity of these procedures was 1 leukemic cell in 103-104 cells and 1 in 104-105 respectively. This study included nine children with APL: six of the patients were treated with multidrug-combined chemotherapy after achieving remission with all-trans retinoic acid (ATRA), two of whom exhibited PCR positivity and subsequently relapsed and treated with an allogeneic bone marrow transplant. No indication of MRD was detected in these patients after transplantation. The remaining three patients received cyclic treatment with alternative chemotherapy and ATRA, in whom MRD was detected in two of these patients and one of them relapsed. Our findings suggest that further treatment may be needed for patiets in danger of relapse as indicated by PCR positivity with an increasing frequency of the PML/RARa gene.
Study on ATRA-resistance caused by mutant PML-RARa; In this study, we examined the cellular and molecular RA-response of a human APL cell line, UF-1, established from a patient who had ATRA-resistance and a mutation in the PML-RARa chimeric protein. For cellular RA-response, differentiation and apoptosis was evaluated in UF-1 cells treated with retinoids. For molecular RA-response, RA-dependent transcriptional activity of PML-RARa chimeric protein was determined. In response to ATRA at 100 nM or lower doses, neither cellular nor molecular RA-response was detected. By contrast, in response to 1 μM RA, UF-1 showed a full-scaled maturation with apoptosis, whereas molecular RA-response of the mutant PML-RARa was insufficient. These findings suggest that the dose-dependently altered ATRA-response of UF-1 cells may be determined through the interaction between the mutant PML-RARa and other intrinsic nuclear RA receptors.
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[Publications] Suzuki H, Imaizumi M, Yoshinari M, Sato A, Rikiishi T, Endo M, Takano T, Shimizu T, Hatae Y, Fujimoto T, Hayashi Y and Iinuma K: "Monitoring of minimal residual disease in children with acute promyelocytic leukemia by RT-PCR detecting PML/RARa chimeric gene: a retrospective study of clinical feasibility"Tohoku J Exp Med. 193. 127-139 (2001)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Kawasaki H, Isoyama K, Eguchi M, Hibi S, Kinukawa N, Kosaka Y, Oda T, Oda M, Nishimura S, Imaizumi M, Okumura T, Hongo T, Okawa H, Mizutani S, Yayashi Y, Tsukimoto I, Kamada N and Ishii E: "A superior outcome of infant acute myeloid leukemia with intensive chemotherapy: Results of the Japan Infant Leukemia Study Group"Blood. 98. 3589-3594 (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] Isoyama K, Eguchi M, Hibi S, Kinukawa N, Okawa H, Kawasaki H, Kosaka Y, Oda T, Oda M, Okamura T, Nishimura S, Hayashi Y, Mori T, Imaizumi M, Mizutani S, Tsukimoto I, Kamada N and Ishii E: "Risk-directed treatment of infant acute lymphoblastic leukaemia based on early assessment of MLL gene status: results of the Japan Infant Leukaemia Study (MLL96)"Br J Haematol. 118. 999-1010 (2002)
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「研究成果報告書概要(欧文)」より
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