title: NOTCH and NF-κB interplay in chronic lymphocytic leukemia is independent of genetic lesion.
abstract: The NOTCH and nuclear factor kappa B (NF-κB) pathways are both constitutively activated in Chronic Lymphocytic Leukemia (CLL). We first described the NOTCH1 PEST domain mutation in a CLL subgroup, but the activation of the NOTCH pathway in NOTCH1-unmutated cases remains unexplained. Here, we investigated whether genetic lesions in the NF-κB/NOTCH loop might support the NOTCH activation status by sequencing negative (TNFAIP3/A20) and positive (TRAF2, TRAF5, TNFRSF11A/RANK, MAP3K7/TAK1, and CARD11) regulators of NF-κB together with NF-κB targets on the NOTCH pathway, the NOTCH ligands Jagged1 and Jagged2, in CLL patients. The sequence analysis revealed four missense mutations for A20, TRAF2, TRAF5 and RANK1 genes, all causing a change in amino acid group from polar to non-polar, but functional domains were not involved. Specific predictive software analyses confirmed that the amino acid changes have a low-functional impact on the protein. Our results show that in CLL, NF-κB regulators and Jagged are both unmutated, suggesting that the Jagged-mediated interplay between NF-κB and NOTCH is independent of genetic lesions.
authors.affiliation: Hematology and Clinical Immunology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Baldoni
authors.forename: Paolo
authors.initials: P
authors.lastname: Sportoletti
authors.forename: Beatrice
authors.initials: B
authors.lastname: Del Papa
authors.forename: Patrizia
authors.initials: P
authors.lastname: Aureli
authors.forename: Erica
authors.initials: E
authors.lastname: Dorillo
authors.forename: Emanuela
authors.initials: E
authors.lastname: Rosati
authors.forename: Raffaella
authors.initials: R
authors.lastname: Ciurnelli
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Marconi
authors.forename: Franca
authors.initials: F
authors.lastname: Falzetti
authors.forename: Mauro
authors.initials: M
authors.lastname: Di Ianni
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D009363:Neoplasm Proteins; D051880:Receptors, Notch