Blood Journal
Leading the way in experimental and clinical research in hematology

Immunobiology
Notch and PI3K: how is the road traveled?

  1. Will Bailis and
  2. Warren S. Pear
  1. UNIVERSITY OF PENNSYLVANIA PERELMAN SCHOOL OF MEDICINE

In this issue of Blood, Wong et al present evidence that the Notch and phosphatidylinositol-3-kinase (PI3K) pathways cross-talk through a Hes1–phosphatase and tensin homolog (PTEN) axis during normal T-cell development.1

Developing thymocytes are guided by inputs from a wide array of signaling pathways, many of which are co-opted by malignant pre-T cells; yet much remains unknown about how these discrete signaling modules are coordinated and integrated to produce a coherent program of T-cell differentiation. The past decade has seen increasing appreciation of the intertwined relationship of the Notch and PI3K signaling pathways in normal and malignant T-cell biology. Both pathways are essential for T-cell development and are critical regulators of survival, growth, and differentiation,2 but the precise manner in which these two pathways converge and/or interact is unclear.

Several lines of evidence now point to a link between the Notch and PI3K pathways via PTEN, a negative regulator of the PI3K pathway. In both acute T-cell leukemia (T-ALL) cell lines and in a Drosophila model of cancer, cells either deficient for Pten or expressing a loss-of-function mutant were resistant to pharmacologic Notch inhibitors. In these contexts, Ferrando and coworkers proposed that the canonical Notch target Hes1 directly repressed Pten expression leading to PI3K activation.3 In the current report, Wong et al present further evidence that Hes1 represses Pten and demonstrate that the Hes1-PTEN axis plays a role in regulating thymocyte development in vitro. Loss of Hes1 activity, by either knockdown or the expression of a dominant-negative Hes1 protein, decreases the efficiency of T-cell development in the OP9-DL1 coculture system. This observation correlates with an increase in Pten transcript and PTEN protein, and decreased phosphorylation of the PI3K pathway target GSK-3β, supporting a model in which Hes1 represses Pten expression. Consistent with the notion that Hes1 regulates Pten, these cells show defective expansion, β-selection, and differentiation to the double positive stage of thymocyte development, even when a TCRβ chain is exogenously expressed. Finally, loss of Pten in DN3 cells allowed thymocytes to bypass the β-selection checkpoint in the absence of Notch signaling. Together, these data support a model in which Notch signaling indirectly regulates the PI3K pathway through a Hes1-PTEN axis, in both normal and malignant contexts.

While these data make a compelling case for Hes1 and PTEN serving as one important node of cross-talk between Notch and PI3K, others also appear to exist. Notch directly up-regulates IL-7 receptor (Il7r) and insulin-like growth factor 1 receptor (Igf1r) expression, and when activated both of these receptors stimulate PI3K signaling.4,5 Notch signaling also up-regulates the mammalian target of rapamycin complex (mTorc), which enhances PI3K signaling in both normal and malignant thymocytes.6,7 Thus, Notch positively reinforces PI3K signaling at multiple junctures (see figure), further supporting a central role for the Notch:PI3K signaling axis in T-cell development and transformation. A collaborative role in transformation is also consistent 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

Notch targets in the PI3K pathway. Shown is a schematic of PI3K signaling molecules that are regulated by the Notch pathway. Notch regulates the receptors IGF1R and IL-7R, both of which stimulate PI3K signaling. In addition, Notch has also been shown to regulate mTorc, a downstream PI3K signaling mediator, and PTEN, a negative regulator of PI3K signaling, through Hes1 repression of Pten transcription.

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 cross-talk 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.

Footnotes

  • Conflict-of-interest disclosure: W.S.P. owns stock in Amgen and Pfizer. W.B. declares no competing financial interests. ■

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