Constitutive activation of NF-κB signaling by NOTCH1 mutations in chronic lymphocytic leukemia

Abstract

NOTCH1 mutations occur in approximately 10% of patients with chronic lymphocytic leukemia (CLL). However, the relationship between the genetic aberrations and tumor cell drug resistance or disease progression remains unclear. Frameshift deletions were detected by gene sequencing in the NOTCH1 PEST domain in three naive CLL patients. These mutations were associated with chromosomal abnormalities including trisomy 12 or 13q deletion. Of note, one of the patients developed Richter’s transformation during FCR treatment. Immunofluorescent and western blot analyses revealed a markedly higher intracellular domain of NOTCH (ICN) expression in the mutated cells compared with their unmutated counterparts and normal CD19+ B lymphocytes (P<0.01 and P<0.001, respectively). In addition, strong DNA-κB binding activities were observed in the mutant cells by gel shift assays. RT-PCR analysis revealed elevated RelA mRNA expression in the mutant cells, while RelB levels were variable. Reduced levels of RelA and RelB mRNA were observed in unmutated CLL and normal B cells. Compared to unmutated CLL and normal B cells, increased apoptosis occurred in the mutant cells in the presence of GSI (ICN inhibitor) and PDTC (NF-κB inhibitor), particularly under the synergistic effects of the two drugs (P=0.03). Moreover, IKKα and IKKβ, the active components in the NF-κB pathway, were markedly inhibited following prolonged treatment with GSI and PDTC. These results suggested that NOTCH1 mutations constitutively activate the NF-κB signaling pathway in CLL, which is likely related to ICN overexpression, indicating NOTCH1 and NF-κB as potential therapeutic targets in the treatment of CLL.

Acute leukemia in a patient with 15q overgrowth syndrome

“…However, these are seldom observed in AML. (Xu et al, ) For the unusual mixed myeloid and lymphoid presentation in this case the degree of contribution of these variants to oncogenesis is not known.…”

Bone marrow stromal cells enhance the survival of chronic lymphocytic leukemia cells by regulating HES‑1 gene expression and H3K27me3 demethylation

“…Co-expression of the Notch receptors and their ligands results in the constitutive activation of the Notch target molecule HES-1, which is a potential biomarker in leukemia cells (22,23). In CLL, upon Notch1 activation, the cleaved intracellular portion of the Notch1 receptor translocates into the nucleus, where it recruits a transcription complex to modify the expression of several target genes, including HES-1, c-MYC and NF-κB (10). Notch1 mutations in CLL have been reported to cause disruptions to HES-1 expression, resulting in the stabilization of active intracellular Notch1 and deregulated Notch signaling (24).…”

“…Notch1 is known to be involved in the pathogenesis of leukemia. Unlike normal B cells, CLL cells express both Notch1 and 2, and their ligands (10). Co-expression of the Notch receptors and their ligands results in the constitutive activation of the Notch target molecule HES-1, which is a potential biomarker in leukemia cells (22,23).…”

“…BMSCs attract and affect CLL cells via G-protein-coupled chemokine receptors, including C-X-C chemokine receptor type 4, cluster of differentiation (CD) 79a and Notch homolog 1, translocation-associated (Drosophila) (Notch1), which are expressed at high levels on CLL cells (8,9). Our group previously reported that Notch1 constitutively activates the nuclear factor (NF)-κB signaling pathway through activating its downstream gene, Hes family BHLH transcription factor 1 (HES-1), in CLL (10). However, the mechanism by which stromal cells affect Notch1-driven oncogenic target gene activation by histone modification is largely unknown.…”

Role of Environmental Chemicals, Processed Food Derivatives, and Nutrients in the Induction of Carcinogenesis

“…Overactivation of EGFR signalling, have been also correlated to the resistance of SP cells derived from head and neck tumors [91]. Moreover, upregulation of Notch signalling has also been described in patients affected by either chronic lymphocytic or T-cell acute lymphoblastic leukemia [92][93][94].…”