Perturbation of lkaros isoform selection by MLV integration is a cooperative event in NotchIC-induced T cell leukemogenesis

The chromosomal translocation t(7;9)(q34;q34.3) in human T cell acute lymphoblastic leukemia (T-ALL) results in the aberrant expression of the intracellular domain of Notch (N-ic). Consistent with the current multistep model for tumorigenesis, mice that express N-ic in T cell progenitors develop a T-ALL-like disease with a lengthened latency. Proviral insertional mutagenesis greatly accelerated the onset of leukemia in N-ic transgenic mice. We demonstrate that the Ikaros (Ik) locus is a common target of proviral integration in N-ic transgenic mice, which results in the loss of Ik DNA binding activity through altered isoform expression. We propose that cooperative leukemogenesis occurs in cells that have constitutive N-ic and altered Ik isoform expression because genes normally repressed by Ik become activated by N-ic/CSL.