NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia

Link between the NOTCH1 and the NF-κ B pathways

D. Benedetti, E. Tissino, F. Pozzo, T. Bittolo, C. Caldana, C. Perini, D. Martorelli, V. Bravin, T. D'Agaro, F. M. Rossi, R. Bomben, E. Santinelli, F. Zaja, G. Pozzato, A. Chiarenza, F. Di Raimondo, G. Del Poeta, D. Rossi, G. Gaidano, M. Dal Bo & 2 others V. Gattei, A. Zucchetto

Research output: Contribution to journalArticle

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-κ B (NF-κ B). Consistently, pharmacological inhibition of the NOTCH1 and/or of the NF-κ B pathways resulted in impaired NF-κ B 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-κ B pathway in CLL.

Original languageEnglish
Pages (from-to)654-662
Number of pages9
JournalLeukemia
Volume32
Issue number3
DOIs
Publication statusPublished - Mar 1 2018

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B-Cell Chronic Lymphocytic Leukemia
Mutation
Trisomy
Integrins
Disease Progression
Pharmacology
Drug Therapy
Genes

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia : Link between the NOTCH1 and the NF-κ B pathways. / Benedetti, D.; Tissino, E.; Pozzo, F.; Bittolo, T.; Caldana, C.; Perini, C.; Martorelli, D.; Bravin, V.; D'Agaro, T.; Rossi, F. M.; 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.; Zucchetto, A.

In: Leukemia, Vol. 32, No. 3, 01.03.2018, p. 654-662.

Research output: Contribution to journalArticle

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 & Zucchetto, A 2018, 'NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia: Link between the NOTCH1 and the NF-κ B pathways', Leukemia, vol. 32, no. 3, pp. 654-662. https://doi.org/10.1038/leu.2017.296
Benedetti, D. ; Tissino, E. ; Pozzo, F. ; Bittolo, T. ; Caldana, C. ; Perini, C. ; Martorelli, D. ; Bravin, V. ; D'Agaro, T. ; Rossi, F. M. ; 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. ; Zucchetto, A. / NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia : Link between the NOTCH1 and the NF-κ B pathways. In: Leukemia. 2018 ; Vol. 32, No. 3. pp. 654-662.
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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-κ B (NF-κ B). Consistently, pharmacological inhibition of the NOTCH1 and/or of the NF-κ B pathways resulted in impaired NF-κ B 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-κ B pathway in CLL.",
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T1 - NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia

T2 - Link between the NOTCH1 and the NF-κ B pathways

AU - Benedetti, D.

AU - Tissino, E.

AU - Pozzo, F.

AU - Bittolo, T.

AU - Caldana, C.

AU - Perini, C.

AU - Martorelli, D.

AU - Bravin, V.

AU - D'Agaro, T.

AU - Rossi, F. M.

AU - Bomben, R.

AU - Santinelli, E.

AU - Zaja, F.

AU - Pozzato, G.

AU - Chiarenza, A.

AU - Di Raimondo, F.

AU - Del Poeta, G.

AU - Rossi, D.

AU - Gaidano, G.

AU - Dal Bo, M.

AU - Gattei, V.

AU - Zucchetto, A.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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-κ B (NF-κ B). Consistently, pharmacological inhibition of the NOTCH1 and/or of the NF-κ B pathways resulted in impaired NF-κ B 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-κ B pathway in CLL.

AB - 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-κ B (NF-κ B). Consistently, pharmacological inhibition of the NOTCH1 and/or of the NF-κ B pathways resulted in impaired NF-κ B 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-κ B pathway in CLL.

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