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.

Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness

“…27,32,33,54 In addition, novel CNAs were identified, which may have a functional impact on the regulation of the NOTCH pathway (RBPJ deletions), 55 the TP53 and/or RB pathway (CDKN2A/B deletions), and the nuclear factor-kB pathway (TRAF2 deletion), 56 recently reported to be involved in FR-CLL. 10,57 In conclusion, this is the first study on a clinically homogeneous group of chemo-refractory CLL cases described from both a mutational and CNA perspective. This effort revealed FAT1 as a new participant to the FR phenomenon, thus paving the way for a thorough examination of the role of the Wnt pathway in the FR event.…”

Wee1 kinase inhibitor MK‑1775 induces apoptosis of acute lymphoblastic leukemia cells and enhances the efficacy of doxorubicin involving downregulation of Notch pathway

“…In B-ALL, Notch-3 and Notch-4 signaling may rescue leukemia cells in contact with human bone marrow-derived mesenchymal stromal cells from apoptosis (47). In addition, Notch has been demonstrated to interact with other signaling pathways in the survival of tumor cells (48,49). It may positively regulate the activity of mTOR pathway in T-ALL (50).…”

Bepridil exhibits anti‐leukemic activity associated with NOTCH1 pathway inhibition in chronic lymphocytic leukemia

“…Leukemic B cells constitutively express NOTCH1/2 receptors, as well as their ligands JAGGED1/2, which lead to the upregulation of the anti‐apoptotic protein Mcl‐1 . Stimulation of CLL cells by NOTCH ligands increases cell survival through activation of the NFkB pathway, whereas NOTCH pathway inhibition accelerates the spontaneous apoptosis of CLL cells …”

“…5 Stimulation of CLL cells by NOTCH ligands increases cell survival through activation of the NFkB pathway, whereas NOTCH pathway inhibition accelerates the spontaneous apoptosis of CLL cells. 6,7 Mutations in the NOTCH1 gene emerged as one of the mechanisms leading to constitutive activation of NOTCH signaling in CLL. [8][9][10] We were the first group to demonstrate recurrent mutations of the C-terminal PEST domain of the protein resulting in impaired NOTCH1 degradation and deregulated signaling.…”