Models of HES1 and PARP1 effects in B-ALL versus T-ALL. On the basis of our findings, we hypothesize that differences in the ratio of PARP1 to HES1 in B-ALL versus T-ALL may partially explain the differences seen in response to Notch/HES1 signaling in these 2 cell types. (A) In B-ALL, low Notch activation and thus low HES1, with higher levels of PARP1, lead to a high PARP1/HES1 ratio. Notch activation leads to HES1 expression, but high PARP1 levels inhibit HES1 function. In addition, increased HES1 induces activation of PARP1, resulting in high PAR levels, leading to nuclear translocation of AIF, caspase activation, PARP1 cleavage, and apoptosis. (B) In contrast, T-ALL have constitutive Notch signaling with high HES1 expression and low PARP1 expression, resulting in a low PARP1/HES1 ratio. Thus, because of a relative lack of PARP1, HES1 repressor function is maintained, and increased HES1 does not lead to significant PARP1 activation or apoptosis. Rather HES1 appears to inhibit apoptosis through repression of phosphatase with tensin homology (PTEN).⁵⁰