Notch and Ikaros: not only converging players in T cell leukemia.
Notch3 overexpression has been observed in virtually 100% of T cell acute lymphoblastic leukemia (T-ALL). A high percentage of infant B- and T-ALLs also display an increased expression of non DNA-binding Ikaros isoforms. It has been suggested that increased expression of non DNA-binding Ikaros isoforms and constitutively activated Notch play a cooperative role in leukemogenesis, converging on the transcriptional regulation of one or more key genes. Thus far however no demonstration of a direct link between aberrant Notch signalling and altered Ikaros isoform expression has been reported. We recently suggested that pre-TCR is the missing link between Notch and Ikaros in T cell leukemogenesis. Our studies demonstrate that the presence of pre-TCR is required to sustain a Notch3-induced altered expression of spliced Ikaros isoforms. Moreover, we identified HuD, an RNA-binding protein able to regulate both mRNA stability and alternative splicing, as the potential pre-TCR-dependent mediator of Notch3 activity. HuD is able to dysregulate the expression pattern of Ikaros isoforms, thus favouring the shift towards non DNA-binding Ikaros isoforms. We finally showed that the increased expression of non DNA-binding Ikaros isoforms is able to restrain the inhibition exerted by Ikaros on Notch3-dependent transcriptional activation of pTa promoter, thus resulting in its significant upregulation. Our findings may help in clarifying the regulatory mechanism of Ikaros alternative splicing and suggest a crosstalk among Notch3, pre-TCR signalling and spliced Ikaros variants in T cell leukemogenesis, mediated by HuD.
Bellavia
Diana
D
Department of Experimental Medicine, University La Sapienza, Roma, taly.
Mecarozzi
Marco
M
Campese
Antonio Francesco
AF
Grazioli
Paola
P
Gulino
Alberto
A
Screpanti
Isabella
I
D000818:Animals; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D051740:Ikaros Transcription Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D051880:Receptors, Notch; D051740:Ikaros Transcription Factor