TitleThe Flt3 internal tandem duplication mutant inhibits the function of transcriptional repressors by blocking interactions with SMRT.
Publication TypeJournal Article
Year of Publication2004
AuthorsTakahashi, Shinichiro, McConnell Melanie J., Harigae Hideo, Kaku Mitsuo, Sasaki Takeshi, Melnick Ari M., and Licht Jonathan D.
JournalBlood
Volume103
Issue12
Pagination4650-8
Date Published2004 Jun 15
ISSN0006-4971
KeywordsAnimals, Cell Division, Cell Line, Cell Line, Tumor, DNA-Binding Proteins, Gene Duplication, Gene Expression Regulation, Gene Silencing, Humans, Kruppel-Like Transcription Factors, Leukemia, Membrane Proteins, Mice, Nuclear Receptor Co-Repressor 2, Promyelocytic Leukemia Zinc Finger Protein, Protein Binding, Recombinant Proteins, Repressor Proteins, Transcription Factors, Transcription, Genetic, Transfection
Abstract

<p>Fms-like tyrosine kinase 3 (Flt3) is a type III receptor tyrosine kinase (RTK). Between 20% and 30% of acute myeloid leukemia (AML) patients have either an internal tandem duplication (ITD) of the juxtamembrane region or a point mutation of the Flt3 receptor leading to the constitutive activation of downstream signaling pathways and aberrant cell growth. The silencing mediator of retinoic and thyroid hormone receptors (SMRT) corepressor mediates transcriptional repression by interacting with transcription factors such as the promyelocytic leukemia zinc finger (PLZF) protein. Previous reports indicate that SMRT interaction with transcription factors can be disrupted by phosphorylation through activation of RTK pathways. We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. Nuclear export was dependent on the SMRT receptor interaction domain (RID), and Flt3-ITD enhances the binding of nuclear-cytoplasm shuttling protein nuclear factor-kappaB-p65 (NFkappaB-p65) to this region. These data suggest that activating mutations of Flt3 may disrupt transcriptional repressor function resulting in aberrant gene regulation and abnormal leukemia cell growth.</p>

DOI10.1182/blood-2003-08-2759
Alternate JournalBlood
PubMed ID14982881
Grant List1R24 CA 095823-01 / CA / NCI NIH HHS / United States
CA 59936 / CA / NCI NIH HHS / United States