In addition, transgenic mice expressing ICN3 develop T-ALL with high penetrance [10], establishing the leukemogenic potential of Notch3. Increased NOTCH3 signaling activity in human cells also can be oncogenic; the human cell line TALL1, which has wild-type NOTCH1 but exhibits sensitivity to gamma secretase inhibitors (GSI; [5, 11]), has a mutation in the NOTCH3 NRR that leads to ligand-independent NOTCH3 activation [11]. Here, NOTCH3 is linked to acute lymphoblastic leukemia.