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: Yovina Sontani, Gavin Chapman, Peter Papathanasiou, Sally Dunwoodie, Christopher C Goodnow, Gerard F Hoyne
• Journal: Leukemia research (Leuk Res) Vol. 35 Issue 11 Pg. 1512-9 (Nov 2011) ISSN: 1873-5835 [Electronic] England
• PMID: 21840596 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• DNA-Binding Proteins
• Hes1 protein, mouse
• Homeodomain Proteins
• Notch1 protein, mouse
• Receptor, Notch1
• Transcription Factor HES-1
• Zfpn1a1 protein, mouse
• Ikaros Transcription Factor
• Luciferases
• Dtx1 protein, mouse
• Ubiquitin-Protein Ligases

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
• Blotting, Western
• Cell Differentiation
• Cells, Cultured
• DNA-Binding Proteins (genetics, metabolism)
• Flow Cytometry
• Homeodomain Proteins (genetics, metabolism)
• Ikaros Transcription Factor (physiology)
• Loss of Heterozygosity
• Luciferases (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mutation (genetics)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (genetics, metabolism)
• Receptor, Notch1 (physiology)
• Thymocytes (pathology)
• Transcription Factor HES-1
• Ubiquitin-Protein Ligases