期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 118, 期 11, 页码 3762-3774出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI34616
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资金
- Fundacao para a Ciencia e a Tecnologia [POC1/SAU-OBS/58913]
- Fundacao Calouste Gulbenkian, Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [OS/02390-4]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [401122/2005-0]
- Medical Research Council [G9403619] Funding Source: researchfish
- MRC [G9403619] Funding Source: UKRI
Mutations in the phosphatase and tensin homolog (PTEN) gene leading to PTEN protein deletion and subsequent activation of the PI3K/Akt signaling pathway are common in cancer. Here we show that PTEN inactivation in human T cell acute lymphoblastic leukemia (T-ALL) cells is not always synonymous with PTEN gene lesions and diminished protein expression. Samples taken from patients with T-ALL at the time of diagnosis very frequently showed constitutive hyperactivation of the PI3K/Akt pathway. In contrast to immortalized cell lines, most primary T-ALL cells did not harbor PTEN gene alterations, displayed normal PTEN mRNA levels, and expressed higher PTEN protein levels than normal T cell precursors. However, PTEN overexpression was associated with decreased PTEN lipid phosphatase activity, resulting from casein kinase 2 (CK2) overexpression and hyperactivation. In addition, T-ALL cells had constitutively high levels of ROS, which can also down-modulate PTEN activity. Accordingly, both CK2 inhibitors and ROS scavengers restored PTEN activity and impaired PI3K/Akt signaling in T-ALL cells. Strikingly, inhibition of PI3K and/or CK2 promoted T-ALL cell death without affecting normal T cell precursors. Overall, our data indicate that T-ALL cells inactivate PTEN mostly in a nondeletional, posttranslational manner. Pharmacological manipulation of these mechanisms may open new avenues for T-ALL treatment.
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