NOTCH and NF-jB interplay in chronic lymphocytic leukemia is independent of genetic lesion Stefano BaldoniPaolo SportolettiBeatrice Del Papa • Patrizia AureliErica DorilloEmanuela RosatiRaffaella Ciurnelli •
2013
The NOTCH and nuclear factor kappa B (NF- jB) 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 investi- gated whether genetic lesions in the NF-jB/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-jB together with NF-jB targets on the NOTCH pathway, the NOTCH ligands Jagged1 and Jag- ged2, 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-jB regulators and Jagged are both unmutated, suggesting that the Jagged- mediated interplay between NF-jB and NOTCH is inde- pendent of genetic lesions.
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