Notch and Ikaros: Not only converging players in T cell leukemia

Diana Bellavia, Marco Mecarozzi, Antonio Francesco Campese, Paola Grazioli, Alberto Gulino, Isabella Screpanti

Research output: Contribution to journalArticle

Abstract

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 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 pTα promoter, thus resulting in its significant upregulation. Our findings may help clarify the regulatory mechanism of Ikaros alternative splicing and suggest a crosstalk between Notch3, pre-TCR signalling and spliced Ikaros variants in T cell leukemogenesis mediated by HuD.

Original languageEnglish
Pages (from-to)2730-2734
Number of pages5
JournalCell Cycle
Volume6
Issue number22
Publication statusPublished - Nov 15 2007

Keywords

  • Ikaros
  • Notch3
  • Pre-TCR
  • RNA binding protein
  • T cell leukemia

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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  • Cite this

    Bellavia, D., Mecarozzi, M., Campese, A. F., Grazioli, P., Gulino, A., & Screpanti, I. (2007). Notch and Ikaros: Not only converging players in T cell leukemia. Cell Cycle, 6(22), 2730-2734.