title: Cooperation between somatic Ikaros and Notch1 mutations at the inception of T-ALL.
abstract: 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 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.
authors.affiliation: Immunology Department, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
authors.forename: Yovina
authors.initials: Y
authors.lastname: Sontani
authors.forename: Gavin
authors.initials: G
authors.lastname: Chapman
authors.forename: Peter
authors.initials: P
authors.lastname: Papathanasiou
authors.forename: Sally
authors.initials: S
authors.lastname: Dunwoodie
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.forename: Gerard F
authors.initials: GF
authors.lastname: Hoyne
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051740:Ikaros Transcription Factor / Q000502:physiology*; D019656:Loss of Heterozygosity; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D051881:Receptor, Notch1 / Q000502:physiology*; D060168:Thymocytes / Q000473:pathology*; D000072056:Transcription Factor HES-1; D044767:Ubiquitin-Protein Ligases
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051740:Ikaros Transcription Factor; D008156:Luciferases; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; D044767:Ubiquitin-Protein Ligases; C489734:Hes1 protein, mouse; C497762:Notch1 protein, mouse; C497238:Zfpn1a1 protein, mouse; C104035:Dtx1 protein, mouse