Thus, by abrogating β-selection and analyzing Notch1 gain of function and Tcf12 loss of function individually, our results unravel a strong selective pressure for down regulation of HEB protein levels driven either by NOTCH1 and/or by pre-TCR signaling as a requirement for progression from the pre-leukemic state to overt T-ALL. Here, TCF12 is linked to acute lymphoblastic leukemia.