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

Authors

Yovina Sontani
Gavin Chapman
Peter Papathanasiou
Sally Dunwoodie
Christopher C. Goodnow
Gerard F. Hoyne, University of Notre Dame AustraliaFollow

Publication Details

Sontani, Y., Chapman, G., Papathanasiou, P., Dunwoodie, S., Goodnow, C. C., & Hoyne, G. F. (2011). Cooperation between somatic Ikaros and Notch1 mutations at the inception of T-ALL. Leukemia Research, 35(11), 1512–1519. doi:10.1016/j.leukres.2011.07.024

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.

Keywords

peer-reviewed