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NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia: link between the NOTCH1 and the NF-κB pathways.

Abstract：

:In chronic lymphocytic leukemia (CLL), stabilizing mutations of NOTCH1, affecting up to 10-15% of cases, have been associated to poor prognosis, disease progression and refractoriness to chemotherapy. NOTCH1 mutations are significantly overrepresented in trisomy 12 CLL, a disease subset frequently expressing CD49d, the α4 chain of the very-late-activation-4 integrin, a well-known key regulator of microenviromental interactions, and negative prognosticator in CLL. In the present study, by analysing a wide cohort of 1180 CLL, we observed a very strong association between the presence of NOTCH1 mutations and the expression of CD49d (P<0.0001), occurring also outside the trisomy 12 CLL subset. Using both the MEC-1 CLL-like cells stably transfected with the NOTCH1 intracellular domain and primary CLL cells bearing a mutated or wild-type NOTCH1 gene configuration, we provide evidence that triggering of the NOTCH1 pathway resulted in a positive CD49d expression regulation, which was driven by a NOTCH1-dependent activation of nuclear factot-κB (NF-κB). Consistently, pharmacological inhibition of the NOTCH1 and/or of the NF-κB pathways resulted in impaired NF-κB nuclear translocation with consequent down-modulation of CD49d expression. Altogether, our data link for the first time NOTCH1 mutations to CD49d expression regulation through the involvement of the NF-κB pathway in CLL.

journal_name

Leukemia

journal_title

Leukemia

authors

Benedetti D,Tissino E,Pozzo F,Bittolo T,Caldana C,Perini C,Martorelli D,Bravin V,D'Agaro T,Rossi FM,Bomben R,Santinelli E,Zaja F,Pozzato G,Chiarenza A,Di Raimondo F,Del Poeta G,Rossi D,Gaidano G,Dal Bo M,Gattei V

doi

10.1038/leu.2017.296

subject

Has Abstract

pub_date

2018-03-01 00:00:00

pages

654-662

issue

3

eissn

0887-6924

issn

1476-5551

pii

leu2017296

journal_volume

32

pub_type

杂志文章

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