Using the mouse model as a unique opportunity to specifically understand initiating events in T-ALL, we unexpectedly found that a hyperactive NOTCH1 allele is devoid of intrinsic reprogramming activity in thymocytes, suggesting that weaker leukemia-associated Notch1 alleles [30] also lack this activity, similar to Notch3[9]. Here, NOTCH3 is linked to acute lymphoblastic leukemia.