NOTCH and NF-κB interplay in chronic lymphocytic leukemia is independent of genetic lesion

• Published in: International journal of hematology Vol. 98; no. 2; pp. 153 - 157
• Main Authors: Baldoni, Stefano, Sportoletti, Paolo, Del Papa, Beatrice, Aureli, Patrizia, Dorillo, Erica, Rosati, Emanuela, Ciurnelli, Raffaella, Marconi, Pierfrancesco, Falzetti, Franca, Di Ianni, Mauro
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 01.08.2013; Springer
• Subjects: Adult; Aged; Amino Acid Substitution; Biological and medical sciences; Female; Hematologic and hematopoietic diseases; Hematology; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Mutation, Missense; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; Oncology; Protein Structure, Tertiary; Rapid Communication; Receptors, Notch - genetics; Receptors, Notch - metabolism; NF-κB; Notch1; CLL; Chronic lymphocytic leukemia; Notch receptor; Hematology; Lymphoproliferative syndrome; Genetics; Malignant hemopathy; Transcription factor NFκB; Lesion; Cancer
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1007/s12185-013-1368-y

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.