Definitive hematopoiesis requires Runx1 C-terminal-mediated subnuclear targeting and transactivation
Authors
Dowdy, Christopher R.Xie, Ronglin
Frederick, Dana
Hussain, Sadiq
Zaidi, Sayyed K.
Vradii, Diana
Javed, Amjad
Li, Xiangen
Jones, Stephen N.
Lian, Jane B.
Van Wijnen, Andre J.
Stein, Janet L.
Stein, Gary S.
UMass Chan Affiliations
Department of Cell BiologyDocument Type
Journal ArticlePublication Date
2010-03-15Keywords
AnimalsCell Line, Tumor
Cell Nucleus
Core Binding Factor Alpha 2 Subunit
Crosses, Genetic
Embryo, Mammalian
Female
Gene Expression Regulation, Developmental
Genotype
*Hematopoiesis
Hematopoietic Stem Cells
Heterozygote
Humans
Male
Mice
Mutant Proteins
Mutation
Protein Binding
Protein Structure, Tertiary
Protein Transport
Structure-Activity Relationship
Transcriptional Activation
Cell Biology
Metadata
Show full item recordAbstract
Runx1 is a key hematopoietic transcription factor required for definitive hematopoiesis and is a frequent target of leukemia-related chromosomal translocations. The resulting fusion proteins, while retaining DNA binding activity, display loss of subnuclear targeting and associated transactivation functions encoded by the C-terminus of the protein. To define the precise contribution of the Runx1 C-terminus in development and leukemia, we created a knock-in mouse with a C-terminal truncation by introducing a single nucleic acid substitution in the native Runx1 locus. This mutation (Runx1(Q307X)) models genetic lesions observed in patients with leukemia and myeloproliferative disorders. The Runx1(Q307X) homozygous mouse exhibits embryonic lethality at E12.5 due to central nervous system hemorrhages and a complete lack of hematopoietic stem cell function. While able to bind DNA, Runx1(Q307X) is unable to activate target genes, resulting in deregulation of various hematopoietic markers. Thus, we demonstrate that the subnuclear targeting and transcriptional regulatory activities of the Runx1 C-terminus are critical for hematopoietic development. We propose that compromising the C-terminal functions of Runx1 is a common mechanism for the pathological consequences of a variety of somatic mutations and Runx1-related leukemic fusion proteins observed in human patients.Source
Hum Mol Genet. 2010 Mar 15;19(6):1048-57. Epub 2009 Dec 24. Link to article on publisher's siteDOI
10.1093/hmg/ddp568Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36006Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1093/hmg/ddp568