title: Mutations in NOTCH1 PEST domain orchestrate CCL19-driven homing of chronic lymphocytic leukemia cells by modulating the tumor suppressor gene DUSP22.
abstract: Even if NOTCH1 is commonly mutated in chronic lymphocytic leukemia (CLL), its functional impact in the disease remains unclear. Using CRISPR/Cas9-generated Mec-1 cell line models, we show that NOTCH1 regulates growth and homing of CLL cells by dictating expression levels of the tumor suppressor gene DUSP22. Specifically, NOTCH1 affects the methylation of DUSP22 promoter by modulating a nuclear complex, which tunes the activity of DNA methyltransferase 3A (DNMT3A). These effects are enhanced by PEST-domain mutations, which stabilize the molecule and prolong signaling. CLL patients with a NOTCH1-mutated clone showed low levels of DUSP22 and active chemotaxis to CCL19. Lastly, in xenograft models, NOTCH1-mutated cells displayed a unique homing behavior, localizing preferentially to the spleen and brain. These findings connect NOTCH1, DUSP22, and CCL19-driven chemotaxis within a single functional network, suggesting that modulation of the homing process may provide a relevant contribution to the unfavorable prognosis associated with NOTCH1 mutations in CLL.
authors.affiliation: Human Genetics Foundation, Turin, Italy.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Arruga
authors.affiliation: Human Genetics Foundation, Turin, Italy.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Gizdic
authors.affiliation: Human Genetics Foundation, Turin, Italy.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bologna
authors.affiliation: Human Genetics Foundation, Turin, Italy.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Cignetto
authors.affiliation: Human Genetics Foundation, Turin, Italy.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Buonincontri
authors.affiliation: Human Genetics Foundation, Turin, Italy.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Serra
authors.affiliation: Human Genetics Foundation, Turin, Italy.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Vaisitti
authors.affiliation: Human Genetics Foundation, Turin, Italy.
authors.forename: K
authors.initials: K
authors.lastname: Gizzi
authors.affiliation: Department of Molecular Biotechnologies and Health Science, University of Turin, Turin, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Vitale
authors.affiliation: Department of Molecular Biotechnologies and Health Science, University of Turin, Turin, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Garaffo
authors.affiliation: Department of Molecular Biotechnologies and Health Science, University of Turin, Turin, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Mereu
authors.affiliation: Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Diop
authors.affiliation: Human Genetics Foundation, Turin, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Neri
authors.affiliation: Human Genetics Foundation, Turin, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Incarnato
authors.affiliation: Department of Molecular Biotechnologies and Health Science, University of Turin, Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Coscia
authors.affiliation: Department of Hematology, Weill Cornell Medicine, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Allan
authors.affiliation: Department of Molecular Biotechnologies and Health Science, University of Turin, Turin, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Piva
authors.affiliation: Human Genetics Foundation, Turin, Italy.|Department of Life Sciences and Systems Biology, University of Turin, Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Oliviero
authors.affiliation: Department of Hematology, Weill Cornell Medicine, New York, NY, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Furman
authors.affiliation: Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Human Genetics Foundation, Turin, Italy.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Deaglio
mesh_terms: D002460:Cell Line; D002465:Cell Movement; D054415:Chemokine CCL19 / Q000502:physiology*; D002633:Chemotaxis; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D054637:Dual-Specificity Phosphatases / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D064593:Heterografts; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology*; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics*; D009154:Mutation; D000072417:Protein Domains / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics*
chemical_list: C515460:CCL19 protein, human; D054415:Chemokine CCL19; C000717967:DNMT3A protein, human; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D054639:Mitogen-Activated Protein Kinase Phosphatases; C442824:DUSP22 protein, human; D054637:Dual-Specificity Phosphatases