2001 Fiscal Year Final Research Report Summary
Point mutations of the AML1 gene in patients with leukemia : implications in leukemogenesis, progression, and recurrence
| Project/Area Number |
12670996
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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 | Kumamoto University |
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Principal Investigator |
ASOU Norio Kumamoto University, School of Medicine, Lecturer, 医学部, 講師 (50175171)
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| Project Period (FY) |
2000 – 2001
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| Keywords | AML1 / PEBP2β / acute myeloblastic leukemia / myelodysplastic syndrome / familial platelet disorder / haploinsufficiency / missense mutation / ミスセンス異変 |
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| Research Abstract |
A Runt domain transeriptibn factor AML1/RUNX1 is essential for generation and differentiation of difinitive hematopoietic stem cells. AML1 is the most frequent target of chromosomal translocations in acute leukemias. Several chimericproteins such as AML1-MTG8 and TEL-AML1 have transdominant properties for wild-type AML1 and acts as transcriptional repressors. On the other hand, mutations in the Runt domain of the AML1 are identified in both sporadic acute myeloblastic leukemia (AML) without AML1 translocation and familial platelet disorder with predisposition to AML (FPD/AML). In this study, we identified mutations of the AML1 gene in 5 of 25 (20%) patients with AML M0 subtype. We also found mutations of the AML1 gene in 2 pidigrees of FPD/AML. These observations indicate that a decrease in AML1 dosage resulting from chromosomal translocations or mutations contributes to leukemogenesis. Functional analysis of AML1 mutants in the FPD/AML pedigrees showed two types of mutations of the AML1 gene : loss-of-function mutations (haploinsufficiency) and a dominant negative forms of mutations. Pedigrees with dominant negative missense mutation of the AML1 appear to have a higher insidence of development of AML than those in families with genuine haploinsufficiency of the AML1 gene such as deletions and frameshift mutations. These observations suggest that dosage of AML1 is critical for acquisition of second mutation leading to AML although this molecular mechanism remains to be determined. Methylation of the p15 gene, which is frequently observed in AML, is candidate for second mutation that should stimulate cell proliferation. We are analyzing p15 mRNA expression in AML by using quantitative assay with real-time RT-PCR. We have also examined mutations of the AML1 gene in patients with acute transformation from myelodysplastic syndrome and relapsing AML.
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Research Products
(13 results)
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[Publications] Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T: "Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies"Blood. 97. 2434-2439 (2001)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Asou N, Adachi K, Tamura J, Kanamaru A, Kageyama S, Hiraoka A, Omoto E, Akiyama H, Tsubaki K, Saito K, Kuriyama K, Oh H, Kitano K, Miyawaki S, Takeyama K, Yamada O, Nishikawa K, Takahashi M, Matsuda S, Ohtake S, Ohno R.: "Analysis of prognostic factors in newly diagnosed patients with acute promyelocytic leukemia : the APL92 study of the Japan Adult Leukemia Study Group (JALSG)"Cancer Chemother Pharmacol. 48 (Suppl 1). S65-S71 (2001)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Naoe T, Tagawa Y, Kiyoi H, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Kusumoto S, Shimazaki C, Saito K, Akiyama H, Motoji T, Nishimura M, Shinagawa K, Ueda R, Saito H, and Ohno R.: "Prognostic significance of the null genotype of glutathione S-transferase-T1 in patients with acute myeloid leukemia : increased early death after chemotherapy"Leukemia. 16. 203-208 (2002)
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「研究成果報告書概要(欧文)」より
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[Publications] Michaud J, Wu F, Osato M, Cottles GM, Yanagida M, Asou N, Shigesada K, Ito Y, Benson KF, Raskind WH, Rossier C, Antonarakis SE, Israels S, McNicol A, Weiss H, Horwitz M, Scott Hs.: "In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia : implications for mechanisms of pathogenesis"Blood. 99. 1364-1372 (2002)
Description
「研究成果報告書概要(欧文)」より
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