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-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.
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
F
F
Pozzo
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
T
T
Bittolo
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
E
E
Vendramini
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
R
R
Bomben
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
P
P
Bulian
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
F M
FM
Rossi
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
A
A
Zucchetto
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
E
E
Tissino
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
M
M
Degan
Department of Onco-Hematology, IRCCS 'Centro di Riferimento Oncologico della Basilicata', Rionero in Vulture, Italy.
G
G
D'Arena
Division of Hematology, Ferrarotto Hospital, Catania, Italy.
F
F
Di Raimondo
Clinica Ematologica, Centro Trapianti e Terapie Cellulari 'Carlo Melzi' DISM, Azienda Ospedaliera Universitaria S Maria Misericordia, Udine, Italy.
F
F
Zaja
Department of Internal Medicine and Hematology, Maggiore General Hospital, University of Trieste, Trieste, Italy.
G
G
Pozzato
Hematology, Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
D
D
Rossi
Department of Translational Medicine, Division of Hematology, University of Eastern Piedmont, Novara, Italy.
G
G
Gaidano
Division of Hematology, S Eugenio Hospital and University of Tor Vergata, Rome, Italy.
G
G
Del Poeta
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
V
V
Gattei
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
M
M
Dal Bo
D049109:Cell Proliferation; D018920:Coculture Techniques; D016259:Genes, myc; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D000090243:Nucleophosmin; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
C497761:NOTCH1 protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D051881:Receptor, Notch1; D000090243:Nucleophosmin