Molecular analysis and clinical evaluation of myelodysplastic syndrome associated gene MLF1
| Project/Area Number |
08457281
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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 |
Hematology
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| Research Institution | Kansai Medical University |
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Principal Investigator |
FUKUHARA Shirou Kansai Medical University, The Depertment of Medicine, Professor, 医学部, 教授 (40142301)
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| Co-Investigator(Kenkyū-buntansha) |
YONEDA-KATO Noriko Kansai Medical University, The Depertment of Medicine, Assistant professor, 医学部, 助手 (10252785)
NOMURA Syousaku Kansai Medical University, The Depertment of Medicine, Associate professor, 医学部, 講師 (20218358)
KISHIMOTO Yuuzi Kansai Medical University, The Depertment of Medicine, Associate professor, 医学部, 講師 (70204857)
足立 昌司 関西医科大学, 医学部, 助手 (00278607)
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| Project Period (FY) |
1996 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 1997: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1996: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | MDS / MLFI / NPM-MLFI / AML / Apoptpsis / Transformation / Molecular analysis / MLF1 / 予後因子 |
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| Research Abstract |
The NPM-MLFI chimeric protein is produced by the t(3 ; 5) (q25.l ; q34) chromosomal translocauion, which is associated with myelodysplastic syndrome (MDS) prior to progression into acute myeloid leukemia (AML). 1. Here we report that K562 human leukemia cells ectopically expressing NPM-MLFI, but not those with wild-type MLFI, were gradually eliminated from the culture by undergoing apoptosis. NIH3T3 mouse Fibroblasts engineered to overexpress NPM-MLFI grew normally but serum deprivation triggered apoptotic cell death with slower kinetics than did other well-known apoptotic inducers such as c-Myc or E2F-1. Quantitative analysis of apoptotic induction confirmed that, neither NPM nor MLFI, but the NPM-MLFI fusion protein was able to induceapoptosis. Analyses using a variety of deletion mutants of NPM-MLFI revealed that induction of apoptosis required the N-terminal domain of MLFI and the NPM domain containing nuclear localization signal and that removal of the NPM dimerization domain mark
… More
edly impaired the ability to induce apoptosis. Co-expression of Bcl-2 rescued NIH3T3 fibroblasts from NPM-MLFI -mediated cell death without affecting the expression level or the subcellular localization of NPM-MLF I and enabled cells to progress into S phase in low serum. These findings provide an NPM-MLFI -mediated novel mechanism of apoptotic induction and imply that NPM-MLFI in collaboration with anti-apoptotic oncoproteins may play an important role in multi-step progression from MDS to AML.
2. The clinical features of t(3 ; 5)-positive myeloid disorders suggest that the chimeric protein is involved in dysregulation of progenitor cells with the capability to differentiate into multiple lineages. So far, involvement of wild-type MLFI in hematopoiesis or in leukemogenesis has not been fully investigated The examination was extended to 65 patients with AML and 44 patients with MDS using the quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method. A high level of MLFI expression was readily detected in the patients with relatively immature AML (M1 and M2), erythroblastic/megakaryoblastic AML (M6 and M7) and post-MDS AML and parients with high risk MDS (RAEB and RAEB-T) but not in those with low risk MDS (RA or RARS), indicating that the pattern of MLFI expression is well identical to the clinical morphology apeared in the t(3 ; 5)-positive myeloid disorders and correlated to the MDS-associated AML and transformation phase of MDS in t(3 ; 5)-negative myeloid disorders. ACD34+ population of normal bone marrow cells preferentially expressed MLFI with obvious decreasing level of expression during the maturation. Therefore, MLFI normally functions in multi-potent progenitor cells and the dysregulation may take a part in leukemogenesis from MDS. Less
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Report
(3 results)
Research Products
(6 results)
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[Publications] Kuefer MU, Look AT, Williams DC, Valentine V, Naeve CW, Behm FG, MUllersman JE, Yoneda-Kato N, Morris SW.: "cDNA cloning, tissue distribution, and chromosomal localization of myelodysplasia/myeloid leukemia factor 2 (MLF2)" Genomics. 35. 392-396 (1996)
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