Perturbation of Ikaros isoform selection by MLV integration is a cooperative event in Notch(IC)-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.
Beverly
Levi J
LJ
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.
Capobianco
Anthony J
AJ
D000208:Acute Disease; D000818:Animals; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers / Q000737:chemistry; D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051740:Ikaros Transcription Factor; D009052:Leukemia Virus, Murine / Q000235:genetics*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020033:Protein Isoforms; D012334:RNA, Neoplasm / Q000235:genetics; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000637:transplantation; D016662:Virus Integration; D016335:Zinc Fingers
C423451:CSL receptor, human; D017931:DNA Primers; D004279:DNA, Viral; D004268:DNA-Binding Proteins; C497239:IKZF1 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D020033:Protein Isoforms; D012334:RNA, Neoplasm; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D014157:Transcription Factors; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor