Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders

Abstract

Purpose of review Highlight recent discoveries about Notch activation and its oncogenic functions in lymphoid malignancies, and discuss the therapeutic potential of Notch inhibition. Recent findings NOTCH mutations arise in a broad spectrum of lymphoid malignancies and are increasingly scrutinized as putative therapeutic targets. In T cell acute lymphoblastic leukemia (T-ALL), NOTCH1 mutations affect the extracellular negative regulatory region and lead to constitutive Notch activation, although mutated receptors remain sensitive to Notch ligands. Other NOTCH1 mutations in T-ALL and NOTCH1/2 mutations in multiple B cell malignancies truncate the C-terminal PEST domain, leading to decreased Notch degradation after ligand-mediated activation. Thus, targeting Notch ligand-receptor interactions could provide therapeutic benefits. In addition, we discuss recent reports on clinical testing of Notch inhibitors in T-ALL that influenced contemporary thinking on the challenges of targeting Notch in cancer. We review advances in the laboratory to address these challenges in regards to drug targets, the Notch-driven metabolome, and the sophisticated protein-protein interactions at Notch-dependent super-enhancers that underlie oncogenic Notch functions. Summary Notch signaling is a recurrent oncogenic pathway in multiple T and B cell lymphoproliferative disorders. Understanding the complexity and consequences of Notch activation is critical to define optimal therapeutic strategies targeting the Notch pathway.

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

“…In B-ALL, chemotherapy upregulates CXCR4 expression in surviving leukemic blasts and accounts for the therapeutic resistance [103]. Recently, Notch signaling has been shown as a common feature in ALL, in particular in more than 60% of T-ALL [104][105][106]. Both hyperactive Notch1 and Notch3 enhances CXCR4 expression in thymus-derived .…”

“…In B-ALL, chemotherapy upregulates CXCR4 expression in surviving leukemic blasts and accounts for the therapeutic resistance [102]. Recently, Notch signaling has been shown as a common feature in ALL, in particular in more than 60% of T-ALL [103][104][105]. Both hyperactive Notch1 and Notch3 enhances CXCR4 expression in thymus-derived and in BM-derived T-cells in T-ALL [106,107], and CXCR4 silencing inhibited the expansion of leukemic cells [106] through disruption of the Notch/CXCR4 partnership [102].…”

FBW7 in hematological tumors (Review)

“…It was reported that >60% of T-ALL cases present with abnormal activation of the Notch1 signaling pathway, indicating that Notch1 might be the most common oncogene in T-ALL (55). Mutations of Notch1 occur mainly in the heterodimeric domain region and the proline, glutamine, serine, and threonine domain (56,57). Activating mutations of Notch1 gene result in sustained expression of genes regulating T cell differentiation, including Hes family bHLH transcription factor 1 and CD25, changing the expression balance of c-Myc and p27 (58-60), upregulating the NF-κB signaling pathway (5), enhancing the expression of the anti-apoptotic X-linked inhibitor of apoptosis protein associated with ubiquitination and degradation, and activating the PKB/Akt/mTOR signaling pathway-mediated inhibition of p53 (61).…”

Deregulation of the Notch pathway as a common road in viral carcinogenesis

“…The best known oncogenic feature linked to Notch pathway is probably the abovementioned NOTCH1 activating translocation present in T‐ALL . Further, truncations of the PEST domain of NOTCH1 and NOTCH2 lead to increased half‐life of NICD, found in some B cell malignancies …”