Therapeutic targeting of the NOTCH1 and neddylation pathways in T cell acute lymphoblastic leukemia

• 成果类型: Article
• 署名作者: Bertulfo, Kalay; Perez-Duran, Pablo; Miller, Hannah; Ma, Cindy; Ambesi-Impiombato, Alberto; Samon, Jeremy; Mackey, Adam; Lin, Wen- Hsuan Wendy; Ferrando, Adolfo A.; Palomero, Teresa
• 署名单位: Columbia University; Columbia University; Columbia University; Columbia University; Bristol-Myers Squibb
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9902
• DOI: 10.1073/pnas.2426742122
• 发表日期: 2025-04-08
• 关键词: gamma-secretase inhibitors; atonal homolog 1; differentiation; stem; homeostasis; activation; modulation; resistance; metaplasia; efficacy

摘要

Gamma Secretase Inhibitors (GSIs) effectively block oncogenic Notch homolog-1 (NOTCH1), a characteristic feature of T cell acute lymphoblastic leukemias (T-ALL). However, their clinical application has been stalled by the induction of severe gastrointestinal toxicity resulting from the inhibition of NOTCH signaling in the gut, which translates into increased goblet cell differentiation. Genome-wide CRISPR loss-of-function screen in the colon cancer cell line LS174T identified the neddylation pathway as a main regulator of goblet cell differentiation upon NOTCH1 inhibition. Consistently, pharmacologic inhibition of the neddylation pathway with the small molecule inhibitor MLN4924, rescued GSI-induced differentiation in LS174T cells. Mechanistically, neddylation inhibition by MLN4924 increases the protein stability of Hairy and enhancer of split-1, a direct NOTCH1 transcriptional target and key regulator of absorptive and secretory cell fate decisions. Combined treatment with GSI and MLN4924 in a murine Notch1-dependent model of T-ALL led to leukemia regression and improved overall survival in the absence of gut toxicity. Overall, these results support the combined targeting of the NOTCH1 and neddylation pathways for the treatment of NOTCH1-induced T-ALL.