Tissue Microenvironment Affects Activity of PTEN in Leukemia

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The tumor suppressor PTEN, which is underexpressed in many cancers, dephosphorylates phosphatidylinositol (3,4,5)-triphosphate and thus inhibits activity of phosphatidylinositol 3-kinases involved in growth factor and survival factor signaling through effectors such as Akt and mTOR. As reported in Nature, Miething and colleagues assessed whether continuous PTEN inactivation is necessary to maintain malignancy.

Using an RNA interference-based transgenic mouse model in which PTEN can be regulated by tetracycline in a time- and tissue-specific manner, they found that PTEN knockdown resulted in disseminated T-cell acute lymphoblastic leukemia in the hematopoietic compartment. Reactivation of PTEN resulted in reduced dissemination but had little effect on tumor load in the hematopoietic organs. Disease infiltration into the intestine was shown to be dependent on CCR9 G-protein-coupled receptor signaling, and this signaling was found to be amplified by PTEN loss.

The investigators concluded, “Our results suggest that in the absence of PTEN, G-protein-coupled receptors may have an unanticipated role in driving tumour growth and invasion in an unsupportive environment. They further reveal that the role of PTEN loss in tumour maintenance is not invariant and can be influenced by the tissue microenvironment, thereby producing a form of intratumoral heterogeneity that is independent of cancer genotype.” ■

Miething C, et al: Nature 509:402-406, 2014.




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