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 language | English |
|---|---|
| Journal | Leukemia |
| DOIs | |
| Publication status | E-pub ahead of print - Mar 21 2017 |
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- 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 journal › Article
}
TY - JOUR
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
Y1 - 2017/3/21
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.
KW - Journal Article
U2 - 10.1038/leu.2017.90
DO - 10.1038/leu.2017.90
M3 - Article
JO - Leukemia
JF - Leukemia
SN - 0887-6924
ER -