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Cooperation between somatic Ikaros and Notch1 mutations at the inception of T-ALL

Sontani, Yovina; Chapman, Gavin; Papathanasiou, Panagiotis; Dunwoodie, Sally; Goodnow, Christopher; Hoyne, Gerard

Description

To understand the interactions between Notch1 and Ikaros in the evolution of T cell acute lymphoblastic leukemia (T-ALL), we traced the evolution of T-ALL in mice with an inherited Ikaros mutation, Ikzf1 Plstc which inactivates DNA binding. DNA-binding Ikaros repressed Notch1 response in transfected cell lines and in CD4 +8 + (DP) thymocytes from young pre-leukemic Ikzf1 Plstc heterozygous mice. In DP thymocytes, a 50-1000 fold escalation in mRNA for Notch1 target genes Hes1 and Dtx1 preceded...[Show more]

dc.contributor.authorSontani, Yovina
dc.contributor.authorChapman, Gavin
dc.contributor.authorPapathanasiou, Panagiotis
dc.contributor.authorDunwoodie, Sally
dc.contributor.authorGoodnow, Christopher
dc.contributor.authorHoyne, Gerard
dc.date.accessioned2015-12-10T21:56:01Z
dc.identifier.issn0145-2126
dc.identifier.urihttp://hdl.handle.net/1885/39229
dc.description.abstractTo understand the interactions between Notch1 and Ikaros in the evolution of T cell acute lymphoblastic leukemia (T-ALL), we traced the evolution of T-ALL in mice with an inherited Ikaros mutation, Ikzf1 Plstc which inactivates DNA binding. DNA-binding Ikaros repressed Notch1 response in transfected cell lines and in CD4 +8 + (DP) thymocytes from young pre-leukemic Ikzf1 Plstc heterozygous mice. In DP thymocytes, a 50-1000 fold escalation in mRNA for Notch1 target genes Hes1 and Dtx1 preceded thymic lymphoma or leukemia and was closely correlated with the first detectable differentiation abnormalities, loss of heterozygosity (LOH) eliminating wild-type Ikzf1, and multiple missense and truncating Notch1 mutations. These findings illuminate the early stages of leukemogenesis by demonstrating progressive exaggeration of Notch1 responsiveness at the DP thymocyte stage brought about by multiple mutations acting in concert upon the Notch1 pathway.
dc.publisherPergamon-Elsevier Ltd
dc.sourceLeukemia Research
dc.subjectKeywords: CD4 antigen; CD8 antigen; Ikaros transcription factor; messenger RNA; Notch1 receptor; acute lymphoblastic leukemia; animal cell; animal experiment; animal model; animal tissue; article; controlled study; DNA binding; Dtx1 gene; gene; gene interaction; ge Ikaros; Leukemia; Notch; T cell; Thymocytes
dc.titleCooperation between somatic Ikaros and Notch1 mutations at the inception of T-ALL
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume35
dc.date.issued2011
local.identifier.absfor110709 - Tumour Immunology
local.identifier.ariespublicationu6800332xPUB173
local.type.statusPublished Version
local.contributor.affiliationSontani, Yovina, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationChapman, Gavin, Victor Chang Cardiac Research Institute
local.contributor.affiliationPapathanasiou, Panagiotis, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationDunwoodie, Sally, Victor Chang Cardiac Research Institute
local.contributor.affiliationGoodnow, Christopher, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationHoyne, Gerard, College of Medicine, Biology and Environment, ANU
local.description.embargo2037-12-31
local.bibliographicCitation.startpage1512
local.bibliographicCitation.lastpage1519
local.identifier.doi10.1016/j.leukres.2011.07.024
local.identifier.absseo920101 - Blood Disorders
local.identifier.absseo920102 - Cancer and Related Disorders
dc.date.updated2016-02-24T11:38:01Z
local.identifier.scopusID2-s2.0-80053993704
local.identifier.thomsonID000296551900033
CollectionsANU Research Publications

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