Journal
CURRENT OPINION IN HEMATOLOGY
Volume 23, Issue 4, Pages 362-370Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/MOH.0000000000000254
Keywords
B cell; leukemia; lymphoma; Notch; T cell
Categories
Funding
- NCI [RO1-CA196604]
- NIAID [RO1-AI091627]
- Leukemia and Lymphoma Society [CDP 1227-14, TRP 6462-15, RSG-11-189-01-TBG]
- Rally Foundation for Childhood Cancer Research/Bear Necessities Pediatric Cancer Foundation
- Concern Foundation
- American Society of Hematology
- American Society for Blood and Marrow Transplantation
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Purpose of review This article highlights recent discoveries about Notch activation and its oncogenic functions in lymphoid malignancies, and discusses 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), NOTCH! mutations affect the extracellular negative regulatory region and lead to constitutive Notch activation, although mutated receptors remain sensitive to Notch ligands. Other NOTCH! mutations in T-ALL and NOTCH 1/2 mutations in multiple B-cell malignancies truncate the C-terminal proline (P), glutamic acid (E), serine (S), threonine (T)-rich (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 superenhancers 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.
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