New mutations stabilize NOTCH1

A leukemia-associated signaling protein accumulates to dangerous levels when its own mutations shield it from degradation. Now, reports from O'Neil et al. (page 1813) and Thompson et al. (page 1825) identify outside forces that also lead to its buildup. Defects in proteasomal targeting, they find, can also trigger leukemia.

T cell acute lymphoblastic leukemia (T-ALL) is triggered by mutations in the NOTCH1 receptor. Once activated, this transmembrane protein is clipped to release its intracellular domain (NICD), which then activates the transcription of genes that goad stem cells to become T cells.

Many transformed T cells have too much NICD, as their NOTCH1 proteins carry mutations that protect them from proteasomal degradation. This increase sends many NOTCH1 targets, particularly oncogenes, into overdrive.

The new reports show that NICD levels are also high in some...