Activating Notch1 mutations are an early event in T-cell malignancy of Ikaros point mutant Plastic/+ mice.
Ikaros and Notch1 genes are critical to T-cell differentiation through transcriptional activation of target genes and interaction with chromatin remodeling complexes. An Ikaros (Plastic) point mutation inhibits activity of normal Ikaros and Ikaros family members, and leads to T-cell lymphoma in heterozygotes (Plstc/+). Analysis revealed Notch1 activating mutations in 12 of 17 Plstc/+ lymphomas (70%), analogous to those in human T-ALL. Mice acquired Notch1 mutations in lymph nodes as early as 7 weeks. Thus, combined Notch1 and Ikaros dysfunction can be a significant early event in T-cell proliferation and tumorigenesis.
Mantha
Simon
S
Department of Medicine, Columbia University, New York, NY 10032, USA.
Ward
Maureen
M
McCafferty
Jonathan
J
Herron
Alan
A
Palomero
Teresa
T
Ferrando
Adolfo
A
Bank
Arthur
A
Richardson
Christine
C
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006579:Heterozygote; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics* / Q000276:immunology; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017354:Point Mutation; D051881:Receptor, Notch1 / Q000235:genetics* / Q000276:immunology; D015533:Transcriptional Activation / Q000235:genetics
C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor