Current views on the role of Notch signaling and the pathogenesis of human leukemia

Abstract

The Notch signaling pathway is highly conserved from Drosophila to humans and plays an important role in the regulation of cellular proliferation, differentiation and apoptosis.Constitutive activation of Notch signaling has been shown to result in excessive cellular proliferation and a wide range of malignancies, including leukemia, glioblastoma and lung and breast cancers. Notch can also act as a tumor suppressor, and its inactivation has been associated with an increased risk of spontaneous squamous cell carcinoma. This minireview focuses on recent advances related to the mechanisms and roles of activated Notch1, Notch2, Notch3 and Notch4 signaling in human lymphocytic leukemia, myeloid leukemia and B cell lymphoma, as well as their significance, and recent advances in Notch-targeted therapies.

Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides

“…44,45 Interestingly, NOTCH2 mutations, gain of function, copy-number gains, and loss of function have been associated with B-cell lymphomas and chronic myelomonocytic leukemia. 46,58,59 We demonstrated germline copy-number gain of both NOTCH2 and NOTCH2NL across all 5 MF tumors, and also identified a NOTCH2 mutation in the negative regulatory region in a separate MF case.…”

“…44,45 Activating mutations in NOTCH2 were implicated in the development of both B-cell lymphomas and murine T-cell leukemia. [45][46][47] In addition to the increased copy numbers of NOTCH2 and NOTCH2NL in all patients subjected to WGS (Figure 4C), we also identified other mutations affecting the Notch pathway.…”

“…44,45 Activating mutations in NOTCH2 were implicated in the development of both B-cell lymphomas and murine T-cell leukemia. [45][46][47] In addition to the increased copy numbers of NOTCH2 and NOTCH2NL in all patients subjected to WGS (Figure 4C), we also identified other mutations affecting the Notch pathway. For example, we identified with targeted ultra-deep sequencing a patient with early plaquestage MF who had a NOTCH2 nonsynonymous SNV (C4699T, R1567W), which is predicted to be deleterious, and is located in the negative regulatory region between 2 previously identified gainof-function mutations found in marginal zone lymphomas.…”

Notch in fibrosis and as a target of anti-fibrotic therapy

“…The Notch receptor can undergo lysosomal degradation involving the ubiquitin ligase Itch/AIP4 or Nedd4, which act together with Numb [30] and Itch/AIP4 [28-30]. GSK3 controls NICD1 ubiquitination and proteasome-mediated degradation by phosphorylation of the NICD and regulates the NICD interaction with the E3 ubiquitin ligase CDC4/FBW7 [32, 33]. …”

Prognostic significance of Notch ligands in patients with non-small cell lung cancer

“…The present study focused on the Notch signaling pathway, which is known to have a significant role in tumorigenesis and cancer progression (7,8). The Notch family consists of four receptors (Notch 1-4) and five ligands (Jag1, Jag2, Dll1, Dll3 and Dll4) (9). Notably, receptors and ligands are typically presented on neighboring cells; therefore, ligand binding is triggered via direct cell-cell communication (10).…”