NOTCH1 mutated chronic lymphocytic leukemia cells are characterized by a MYC-related overexpression of nucleophosmin-1 and ribosome associated components

F Pozzo, T Bittolo, E. Vendramini, R Bomben, P Bulian, F M Rossi, A Zucchetto, E Tissino, M Degan, G D'Arena, F. Di Raimondo, Francesco Zaja, Gabriele Pozzato, D Rossi, G. Gaidano, Giovanni Del Poeta, V Gattei, M Dal Bo

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Abstract

In chronic lymphocytic leukemia (CLL), the mechanisms controlling cell growth and proliferation in presence of NOTCH1 mutations remain largely unexplored. By performing a gene expression profile of NOTCH1 mutated (NOTCH1-mut) versus NOTCH1 wild type CLL, we identified a gene signature of NOTCH1-mut CLL characterized by upregulation of genes related to ribosome biogenesis, such as nucleophosmin1 (NPM1) and ribosomal proteins (RNPs). Activation of NOTCH1 signaling by EDTA or by co-culture with JAGGED1-expressing stromal cells increased NPM1 expression, and inhibition of NOTCH1 signaling by either NOTCH1-specific small interfering RNA (siRNA) or γ-secretase inhibitor reduced NPM1 expression. Bioinformatic analyses and in-vitro activation/inhibition of NOTCH1 signaling suggested a role of MYC as mediator of NOTCH1 effects over NPM1 and RNPs expression in NOTCH1-mut CLL. Chromatin immunoprecipitation experiments performed on NOTCH1 intracellular domain (NICD)-transfected CLL-like cells showed the direct binding of NOTCH1 to the MYC promoter, and transfection with MYC-specific siRNA reduced NPM1 expression. In turn, NPM1 determined a proliferation advantage of CLL-like cells, as demonstrated by NPM1-specific siRNA transfection. In conclusion, NOTCH1 mutations in CLL are associated with the overexpression of MYC and MYC-related genes involved in protein biosynthesis including NPM1, which are allegedly responsible for cell growth and/or proliferation advantages of NOTCH1-mut CLL.Leukemia accepted article preview online, 21 March 2017. doi:10.1038/leu.2017.90.

Original languageEnglish
JournalLeukemia
DOIs
Publication statusE-pub ahead of print - Mar 21 2017

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B-Cell Chronic Lymphocytic Leukemia
Ribosomes
Small Interfering RNA
Transfection
Genes
Amyloid Precursor Protein Secretases
Mutation
nucleophosmin
Chromatin Immunoprecipitation
Ribosomal Proteins
Protein Biosynthesis
Stromal Cells
Growth
Coculture Techniques
Computational Biology
Transcriptome
Edetic Acid
Leukemia
Up-Regulation
Cell Proliferation

Keywords

  • Journal Article

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NOTCH1 mutated chronic lymphocytic leukemia cells are characterized by a MYC-related overexpression of nucleophosmin-1 and ribosome associated components. / Pozzo, F; Bittolo, T; Vendramini, E.; Bomben, R; Bulian, P; Rossi, F M; Zucchetto, A; Tissino, E; Degan, M; D'Arena, G; Di Raimondo, F.; Zaja, Francesco; Pozzato, Gabriele; Rossi, D; Gaidano, G.; Del Poeta, Giovanni; Gattei, V; Dal Bo, M.

In: Leukemia, 21.03.2017.

Research output: Contribution to journalArticle

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title = "NOTCH1 mutated chronic lymphocytic leukemia cells are characterized by a MYC-related overexpression of nucleophosmin-1 and ribosome associated components",
abstract = "In chronic lymphocytic leukemia (CLL), the mechanisms controlling cell growth and proliferation in presence of NOTCH1 mutations remain largely unexplored. By performing a gene expression profile of NOTCH1 mutated (NOTCH1-mut) versus NOTCH1 wild type CLL, we identified a gene signature of NOTCH1-mut CLL characterized by upregulation of genes related to ribosome biogenesis, such as nucleophosmin1 (NPM1) and ribosomal proteins (RNPs). Activation of NOTCH1 signaling by EDTA or by co-culture with JAGGED1-expressing stromal cells increased NPM1 expression, and inhibition of NOTCH1 signaling by either NOTCH1-specific small interfering RNA (siRNA) or γ-secretase inhibitor reduced NPM1 expression. Bioinformatic analyses and in-vitro activation/inhibition of NOTCH1 signaling suggested a role of MYC as mediator of NOTCH1 effects over NPM1 and RNPs expression in NOTCH1-mut CLL. Chromatin immunoprecipitation experiments performed on NOTCH1 intracellular domain (NICD)-transfected CLL-like cells showed the direct binding of NOTCH1 to the MYC promoter, and transfection with MYC-specific siRNA reduced NPM1 expression. In turn, NPM1 determined a proliferation advantage of CLL-like cells, as demonstrated by NPM1-specific siRNA transfection. In conclusion, NOTCH1 mutations in CLL are associated with the overexpression of MYC and MYC-related genes involved in protein biosynthesis including NPM1, which are allegedly responsible for cell growth and/or proliferation advantages of NOTCH1-mut CLL.Leukemia accepted article preview online, 21 March 2017. doi:10.1038/leu.2017.90.",
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T1 - NOTCH1 mutated chronic lymphocytic leukemia cells are characterized by a MYC-related overexpression of nucleophosmin-1 and ribosome associated components

AU - Pozzo, F

AU - Bittolo, T

AU - Vendramini, E.

AU - Bomben, R

AU - Bulian, P

AU - Rossi, F M

AU - Zucchetto, A

AU - Tissino, E

AU - Degan, M

AU - D'Arena, G

AU - Di Raimondo, F.

AU - Zaja, Francesco

AU - Pozzato, Gabriele

AU - Rossi, D

AU - Gaidano, G.

AU - Del Poeta, Giovanni

AU - Gattei, V

AU - Dal Bo, M

PY - 2017/3/21

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N2 - In chronic lymphocytic leukemia (CLL), the mechanisms controlling cell growth and proliferation in presence of NOTCH1 mutations remain largely unexplored. By performing a gene expression profile of NOTCH1 mutated (NOTCH1-mut) versus NOTCH1 wild type CLL, we identified a gene signature of NOTCH1-mut CLL characterized by upregulation of genes related to ribosome biogenesis, such as nucleophosmin1 (NPM1) and ribosomal proteins (RNPs). Activation of NOTCH1 signaling by EDTA or by co-culture with JAGGED1-expressing stromal cells increased NPM1 expression, and inhibition of NOTCH1 signaling by either NOTCH1-specific small interfering RNA (siRNA) or γ-secretase inhibitor reduced NPM1 expression. Bioinformatic analyses and in-vitro activation/inhibition of NOTCH1 signaling suggested a role of MYC as mediator of NOTCH1 effects over NPM1 and RNPs expression in NOTCH1-mut CLL. Chromatin immunoprecipitation experiments performed on NOTCH1 intracellular domain (NICD)-transfected CLL-like cells showed the direct binding of NOTCH1 to the MYC promoter, and transfection with MYC-specific siRNA reduced NPM1 expression. In turn, NPM1 determined a proliferation advantage of CLL-like cells, as demonstrated by NPM1-specific siRNA transfection. In conclusion, NOTCH1 mutations in CLL are associated with the overexpression of MYC and MYC-related genes involved in protein biosynthesis including NPM1, which are allegedly responsible for cell growth and/or proliferation advantages of NOTCH1-mut CLL.Leukemia accepted article preview online, 21 March 2017. doi:10.1038/leu.2017.90.

AB - In chronic lymphocytic leukemia (CLL), the mechanisms controlling cell growth and proliferation in presence of NOTCH1 mutations remain largely unexplored. By performing a gene expression profile of NOTCH1 mutated (NOTCH1-mut) versus NOTCH1 wild type CLL, we identified a gene signature of NOTCH1-mut CLL characterized by upregulation of genes related to ribosome biogenesis, such as nucleophosmin1 (NPM1) and ribosomal proteins (RNPs). Activation of NOTCH1 signaling by EDTA or by co-culture with JAGGED1-expressing stromal cells increased NPM1 expression, and inhibition of NOTCH1 signaling by either NOTCH1-specific small interfering RNA (siRNA) or γ-secretase inhibitor reduced NPM1 expression. Bioinformatic analyses and in-vitro activation/inhibition of NOTCH1 signaling suggested a role of MYC as mediator of NOTCH1 effects over NPM1 and RNPs expression in NOTCH1-mut CLL. Chromatin immunoprecipitation experiments performed on NOTCH1 intracellular domain (NICD)-transfected CLL-like cells showed the direct binding of NOTCH1 to the MYC promoter, and transfection with MYC-specific siRNA reduced NPM1 expression. In turn, NPM1 determined a proliferation advantage of CLL-like cells, as demonstrated by NPM1-specific siRNA transfection. In conclusion, NOTCH1 mutations in CLL are associated with the overexpression of MYC and MYC-related genes involved in protein biosynthesis including NPM1, which are allegedly responsible for cell growth and/or proliferation advantages of NOTCH1-mut CLL.Leukemia accepted article preview online, 21 March 2017. doi:10.1038/leu.2017.90.

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