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dc.contributor.authorDowdy, Christopher R.
dc.contributor.authorFrederick, Dana
dc.contributor.authorZaidi, Sayyed K.
dc.contributor.authorColby, Jennifer L.
dc.contributor.authorLian, Jane B.
dc.contributor.authorvan Wijnen, Andre J.
dc.contributor.authorGerstein, Rachel M.
dc.contributor.authorStein, Janet L.
dc.contributor.authorStein, Gary S.
dc.date2022-08-11T08:08:29.000
dc.date.accessioned2022-08-23T15:57:10Z
dc.date.available2022-08-23T15:57:10Z
dc.date.issued2013-11-01
dc.date.submitted2014-05-13
dc.identifier.citationDowdy CR, Frederick D, Zaidi SK, Colby JL, Lian JB, van Wijnen AJ, Gerstein RM, Stein JL, Stein GS. A germline point mutation in Runx1 uncouples its role in definitive hematopoiesis from differentiation. Exp Hematol. 2013 Nov;41(11):980-991.e1. doi: 10.1016/j.exphem.2013.06.006. <a href="http://dx.doi.org/10.1016/j.exphem.2013.06.006">Link to article on publisher's site</a>
dc.identifier.issn0301-472X (Linking)
dc.identifier.doi10.1016/j.exphem.2013.06.006
dc.identifier.pmid23823022
dc.identifier.urihttp://hdl.handle.net/20.500.14038/30134
dc.description.abstractDefinitive hematopoiesis requires the master hematopoietic transcription factor Runx1, which is a frequent target of leukemia-related chromosomal translocations. Several of the translocation-generated fusion proteins retain the DNA binding activity of Runx1, but lose subnuclear targeting and associated transactivation potential. Complete loss of these functions in vivo resembles Runx1 ablation, which causes embryonic lethality. We developed a knock-in mouse that expresses full-length Runx1 with a mutation in the subnuclear targeting cofactor interaction domain, Runx1(HTY350-352AAA). Mutant mice survive to adulthood, and hematopoietic stem cell emergence appears to be unaltered. However, defects are observed in multiple differentiated hematopoietic lineages at stages where Runx1 is known to play key roles. Thus, a germline mutation in Runx1 reveals uncoupling of its functions during developmental hematopoiesis from subsequent differentiation across multiple hematopoietic lineages in the adult. These findings indicate that subnuclear targeting and cofactor interactions with Runx1 are important in many compartments throughout hematopoietic differentiation. Elsevier Inc. All rights reserved.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=23823022&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1016/j.exphem.2013.06.006
dc.subjectAnimals
dc.subjectB-Lymphocytes
dc.subjectCell Differentiation
dc.subjectCell Proliferation
dc.subjectCells, Cultured
dc.subjectCore Binding Factor Alpha 2 Subunit
dc.subjectEmbryo, Mammalian
dc.subjectFlow Cytometry
dc.subjectGene Expression Regulation, Developmental
dc.subject*Germ-Line Mutation
dc.subjectHematopoiesis
dc.subjectHematopoietic Stem Cells
dc.subjectLymphopoiesis
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMice, Transgenic
dc.subjectMicroscopy, Fluorescence
dc.subject*Point Mutation
dc.subjectReverse Transcriptase Polymerase Chain Reaction
dc.subjectT-Lymphocytes
dc.subjectCell Biology
dc.subjectCellular and Molecular Physiology
dc.subjectDevelopmental Biology
dc.titleA germline point mutation in Runx1 uncouples its role in definitive hematopoiesis from differentiation
dc.typeJournal Article
dc.source.journaltitleExperimental hematology
dc.source.volume41
dc.source.issue11
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/373
dc.identifier.contextkey5574351
html.description.abstract<p>Definitive hematopoiesis requires the master hematopoietic transcription factor Runx1, which is a frequent target of leukemia-related chromosomal translocations. Several of the translocation-generated fusion proteins retain the DNA binding activity of Runx1, but lose subnuclear targeting and associated transactivation potential. Complete loss of these functions in vivo resembles Runx1 ablation, which causes embryonic lethality. We developed a knock-in mouse that expresses full-length Runx1 with a mutation in the subnuclear targeting cofactor interaction domain, Runx1(HTY350-352AAA). Mutant mice survive to adulthood, and hematopoietic stem cell emergence appears to be unaltered. However, defects are observed in multiple differentiated hematopoietic lineages at stages where Runx1 is known to play key roles. Thus, a germline mutation in Runx1 reveals uncoupling of its functions during developmental hematopoiesis from subsequent differentiation across multiple hematopoietic lineages in the adult. These findings indicate that subnuclear targeting and cofactor interactions with Runx1 are important in many compartments throughout hematopoietic differentiation. Elsevier Inc. All rights reserved.</p>
dc.identifier.submissionpathfaculty_pubs/373
dc.contributor.departmentDepartment of Microbiology and Physiological Systems
dc.contributor.departmentDepartment of Cell and Developmental Biology
dc.source.pages980-991.e1


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