Notch target gene deregulation and maintenance of the leukemogenic phenotype do not require RBP-J kappa in Ikaros null mice.
Ikaros and Notch are transcriptional regulators essential for normal T cell development. Aberrant activation of Notch target genes is observed in Ikaros-deficient thymocytes as well as leukemia cell lines. However, it is not known whether Notch deregulation plays a preferential or obligatory role in the leukemia that arise in Ikaros null (Ik(-/-)) mice. To answer this question, the expression of the DNA-binding Notch target gene activator RBP-Jkappa was abrogated in Ik(-/-) double-positive thymocytes. This was accomplished through conditional inactivation using CD4-Cre transgenic mice containing floxed RBP-Jkappa alleles (RBPJ(fl/fl)). Ik(-/-) x RBPJ(fl/fl) x CD4-Cre(+) transgenic mice develop clonal T cell populations in the thymus that escape to the periphery, with similar kinetics and penetrance as their CD4-Cre(-) counterparts. The clonal populations do not display increased RBP-Jkappa expression compared with nontransformed thymocytes, suggesting there is no selection for clones that have not fully deleted RBP-Jkappa. However, RBPJ-deficient clonal populations do not expand as aggressively as their RBPJ-sufficient counterparts, suggesting a qualitative role for deregulated Notch target gene activation in the leukemogenic process. Finally, these studies show that RBP-Jkappa plays no role in Notch target gene repression in double-positive thymocytes but rather that it is Ikaros that is required for the repression of these genes at this critical stage of T cell development.
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Sheila
S
Chari
Sarah E
SE
Umetsu
Susan
S
Winandy
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D020868:Gene Silencing / Q000276:immunology; D018390:Gene Targeting; D051740:Ikaros Transcription Factor / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016130:Immunophenotyping; D007942:Leukemia, Experimental / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor