16 AUGUST 2012 I VOLUME 120, NUMBER 7 with past work showing that loss of Pten in Notch-initiated tumors accelerates leukemogenesis, and that treatment of T-ALL with both Notch and mTor inhibitors synergizes to suppress tumor survival and proliferation. 8, 9 However, the relative importance of each point of cross-talk is unclear, and in fact the answer may vary depending on the experimental system that is used. For example, conditional Hes1 knockout mice fail to display alterations in PI3K signaling, while other analyses of primary murine tumors and T-ALL cell lines found no correlation between PTEN expression and sensitivity to Notch inhibition. 8, 10 Additional studies are necessary to delineate the extent to which Notch and PI3K signaling overlap functionally and whether points of crosstalk are context specific. These details are likely to affect the design and outcome of attempts to target the Notch: PI3K pathway in Notch-dependent T-ALLs and other human disorders marked by aberrant increases in Notch and PI3K signaling.