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

Area of Science:

• Oncology
• Molecular Biology
• Gastroenterology

Background:

• Gamma Secretase Inhibitors (GSIs) target oncogenic NOTCH1 in T cell acute lymphoblastic leukemia (T-ALL).
• Clinical use of GSIs is limited by gastrointestinal toxicity due to NOTCH signaling inhibition in the gut, causing goblet cell differentiation.
• The neddylation pathway's role in goblet cell differentiation upon NOTCH1 inhibition was investigated.

Purpose of the Study:

• To identify mechanisms regulating goblet cell differentiation during NOTCH1 inhibition.
• To evaluate the therapeutic potential of combining NOTCH1 and neddylation pathway inhibition for T-ALL treatment.

Main Methods:

• Genome-wide CRISPR loss-of-function screen in LS174T colon cancer cells.
• Pharmacologic inhibition of the neddylation pathway using MLN4924.
• Assessment of Hairy and enhancer of split-1 protein stability.
• Evaluation of combined GSI and MLN4924 treatment in a murine T-ALL model.

Main Results:

• The neddylation pathway was identified as a key regulator of goblet cell differentiation following NOTCH1 inhibition.
• MLN4924 treatment rescued GSI-induced goblet cell differentiation in vitro.
• MLN4924 increased the stability of Hairy and enhancer of split-1, a NOTCH1 target.
• Combined GSI and MLN4924 treatment led to leukemia regression and improved survival in mice without gut toxicity.

Conclusions:

• Targeting the neddylation pathway can mitigate GSI-induced gastrointestinal toxicity.
• Combined inhibition of NOTCH1 and neddylation pathways offers a promising therapeutic strategy for T-ALL.