NOTCH signaling in the pathogenesis of splenic marginal zone lymphoma—opportunities for therapy

Abstract

NOTCH signaling is a highly conserved pathway mediated by four receptors (NOTCH 1–4) playing critical functions in proliferation, differentiation, and cell death. Under physiologic circumstances, NOTCH2 is a key regulator in marginal zone differentiation and development. Over the last decade, growing data demonstrated frequent NOTCH2 mutations in splenic marginal zone lymphoma (SMZL) underscoring its critical role in the pathogenesis of this disease. Moreover, NOTCH2 specificity across studies supports the rationale to assess its value as a diagnosis biomarker in a disease without pathognomonic features. These data make NOTCH signaling an appealing target for drug discovery in SMZL; however, prior efforts attempting to manipulate this pathway failed to demonstrate meaningful clinical benefit, or their safety profile prevented further development. In this review, we discuss the current knowledge of NOTCH implications in the pathogenesis and as a potential druggable target in SMZL.

Keywords:

• NOTCH signaling
• splenic marginal zone lymphoma
• pathogenesis

Disclosure statement

J.P.A. has received honoraria from OncLive and Oncinfo and has served on the advisory board of ADC Therapeutics. An immediate family member has served on the advisory boards of Puma Biotechnology, Inovio Pharmaceuticals, Agios Pharmaceuticals, Forma Therapeutics, and Foundation Medicine. I.S.L. has served on the advisory boards of Seattle Genetics, Janssen Scientific, and Verastem.

Additional information

Funding

J.P.A. is a K12 Scholar supported by the National Cancer Institute of the National Institutes of Health under Award Number K12CA226330. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. I.S.L. is supported by grant 1R01CA233945 from the National Cancer Institute, the Dwoskin, and Anthony Rizzo Families Foundations and Jaime Erin Follicular Lymphoma Research Consortium.