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

In chronic lymphocytic leukemia (CLL), the mechanisms controlling cell growth and proliferation in the 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-...

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Bibliographic Details
Published in:Leukemia 2017-11, Vol.31 (11), p.2407-2415
Main Authors: 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, F, Pozzato, G, Rossi, D, Gaidano, G, Del Poeta, G, Gattei, V, Dal Bo, M
Format: Article
Language:English
Subjects:
Acetic acid
Analysis
Biosynthesis
Cell growth
Cell Proliferation
Chromatin
Chronic lymphocytic leukemia
Coculture Techniques
Development and progression
Evolution
Gene expression
Gene mutation
Genes
Genes, myc
Genetic aspects
Humans
Immunoprecipitation
Inhibition
Jagged1 protein
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell - genetics
Leukemia, Lymphocytic, Chronic, B-Cell - metabolism
Leukemia, Lymphocytic, Chronic, B-Cell - pathology
Lymphatic leukemia
Mutation
Myc protein
Notch1 protein
Nuclear Proteins - metabolism
Physiological aspects
Protein biosynthesis
Proteins
Receptor, Notch1 - genetics
Receptor, Notch1 - metabolism
Ribonucleic acid
Ribosomal proteins
Ribosomes - metabolism
RNA
Secretase
Signal Transduction
Signaling
siRNA
Stromal cells
Transfection
Tumor Cells, Cultured
Up-Regulation
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Summary:In chronic lymphocytic leukemia (CLL), the mechanisms controlling cell growth and proliferation in the 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 the upregulation of genes related to ribosome biogenesis, such as nucleophosmin 1 (NPM1) and ribosomal proteins (RNPs). Activation of NOTCH1 signaling by ethylenediaminetetraacetic acid or by coculture 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 a mediator of NOTCH1 effects over NPM1 and RNP 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.
ISSN:0887-6924
1476-5551
DOI:10.1038/leu.2017.90