Stephen Jones Lab Publications
Title
Definitive hematopoiesis requires Runx1 C-terminal-mediated subnuclear targeting and transactivation
UMMS Affiliation
Department of Cell Biology
Publication Date
2010-03-15
Document Type
Article
Subjects
Animals; Cell 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
Disciplines
Cell Biology
Abstract
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.
DOI of Published Version
10.1093/hmg/ddp568
Source
Hum Mol Genet. 2010 Mar 15;19(6):1048-57. Epub 2009 Dec 24. Link to article on publisher's site
Journal/Book/Conference Title
Human molecular genetics
Related Resources
Repository Citation
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.; and Stein, Gary S., "Definitive hematopoiesis requires Runx1 C-terminal-mediated subnuclear targeting and transactivation" (2010). Stephen Jones Lab Publications. 10.
https://escholarship.umassmed.edu/jones/10