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analysis of leukemogenesis by MELS in MEL-EVI1 gene family

Research Project

Project/Area Number 18591075
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionUniversity of Miyazaki

Principal Investigator

NISHIKATA Ichiro  University of Miyazaki, Medicine, Research associate (50253844)

Co-Investigator(Kenkyū-buntansha) KAZUHIRO Morishita  University of Miyazaki, Medicine, Professor (80260321)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,350,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥450,000)
Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Keywordsleukemogenesis / t(1 : 3) translocation / MEL1 (PRDM16) / GATA-2 gene regulation / MEL1 (PRDM16) / 発現制御
Research Abstract

The MDS1/EVI1-like gene 1 (MEL1) was identified as transcriptional regulator that was the causative factor in pathogenesis of the t (1 ; 3) (p36 ; q21)-positive acute myeloid leukemia. However, the molecular basis of their transcriptional functions has remained elusive. Recently, we have shown that the ecotropic virus integration site-1 (EVI1) binds to its DNA consensus sequence located around 6-7 kb upstream region of the GATA-2 IS exon and up-regulates the expression of GATA-2 gene in EML-C1, a murine multipotent progenitor cell line (Yuasa, et. al., 2005). In contrast, Overexpression of MEL1S, PR domain-defective short form in L-G3, a IL-3-dependent murine myeloid cell line, blocks G-CSF-induced myeloid differentiation and down-regulate the expression of GATA-2 gene. To determine whether the binding of MEL1S to CtBP is required for action of MEL1S in GATA-2 gene regulation, We created CtBP-binding-deficient mutant of MEL1S (PFAST/PLASS).With the reporter gene containing 0〜7 kb upstream region of the GATA-2 IS exon, This wild-type and the mutant of MELlS were ectopically expressed in L-G3 cells as above and 293T, HeLa, COS7, CHO cells, authentic fibroblast cell lines, respectively. When wild-type and the mutant of MEL1S was transiently expressed in L-G3 cells, wild-type MEL1S significantly reduced the activity of GATA-2 IS promoter by 70%, but the repression was greatly reduced in cells expressing mutant MELlS (40% reduction). By the other hand, the activity of GATA-2 IS promoter was not suppressed by the mutant MEL1S that does not bind CtBP in fibroblast cells tested, when wild-type MEL1S slightly reduced by 30%. These findings highlight the relationship between the expression of GATA-2 gene regulated by MEL1S and the interaction of MEL1S and HDAC and how these factors affect the gene expression and leukemogenesis of MEL1S in leukemia cells.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report

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Published: 2006-04-01   Modified: 2016-04-21  

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