High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia

Abstract

To more comprehensively assess the pathogenic contribution of the PTEN-PI3K-AKT pathway to T-cell acute lymphoblastic leukemia (T-ALL), we examined diagnostic DNA samples from children with T-ALL using array comparative genomic hybridization and sequence analysis. Alterations of PTEN, PI3K, or AKT were identified in 47.7% of 44 cases.There was a striking clustering of PTEN mutations in exon 7 in 12 cases, all of which were predicted to truncate the C2 domain without disrupting the phosphatase domain of PTEN. Induction chemotherapy failed to induce remission in 3 of the 4 patients whose lymphoblasts harbored PTEN deletions at the time of diagnosis, compared with none of the 12 patients with mutations of PTEN exon 7 (P ‫؍‬ .007), suggesting that PTEN deletion has more adverse therapeutic consequences than mutational disruptions that preserve the phosphatase domain. These findings add significant support to the rationale for the development of therapies targeting the PTEN-PI3K-AKT pathway in T-ALL. IntroductionDespite recent improvements in therapy, approximately 25% of children and 50% to 70% of adults with T-cell acute lymphoblastic leukemia (T-ALL) develop treatment-resistant disease, 1,2 which carries a dire prognosis. 3 Molecularly targeted agents hold considerable promise for the treatment of T-ALL, although limits in our current understanding of the key pathways that drive T-ALL pathogenesis restrict our ability to use these agents effectively.PTEN is a negative regulator of oncogenic PI3K-AKT signaling, 4 and recent studies have demonstrated the inactivation of PTEN in human T-ALL cell lines and primary samples. [5][6][7][8] Furthermore, the inactivation of PTEN has been shown to play a prominent role in resistance to NOTCH inhibition in T-ALL cell lines, an effect that appears to be mediated by AKT. 7 The activation of PI3K-AKT signaling can also occur by mutation of PI3K or AKT genes, which have not previously been assessed in T-ALL. Finally, the spectrum of PTEN mutations has not been extensively analyzed in clinical samples of primary T-ALL. Here we investigated the frequency and prognostic implications of PTEN, PI3K, and AKT abnormalities in childhood T-ALL, using array comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), and sequence analysis.

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…21,22,25,26 Thus, PTEN is an enticing therapeutic target for activation as it is frequently inactivated in many human cancers through point mutations as well as other means (for example, promoter hypermethylation, gene deletion) and its inactivation results in elevated Akt activity and abnormal growth regulation. 21,22,27,28 Moreover, PTEN can be inactivated by phosphorylation and oxidation in human cancer and which results in elevated Akt activity and abnormal growth regulation. 29 Some cells become therapy resistant by inactivation of PTEN.…”

Inhibition of Akt Potentiates 2-DG–Induced Apoptosis via Downregulation of UPR in Acute Lymphoblastic Leukemia

“…A number of ALL phenotypes exhibit mutations that lead to inactivation or constitutive activation of oncogenic pathways such as LKB1, PTEN, PI3K/Akt and RAS, which have been linked to the regulation of energy metabolism in general and glucose metabolism in particular (4)(5)(6). T-ALL is known to have a high rate of PTEN mutations that lead to constitutive activation of Akt (7). Our laboratory has previously shown that the master energy regulator AMPK has significant feedforward and feedback cross-talk with these pathways and that AMPK is a suitable target for ALL therapy (8,9).…”

Negative prognostic impact of PTEN mutation in pediatric T-cell acute lymphoblastic leukemia

“…1 However, a Letters to the Editor relatively small but significant subset of newly diagnosed T-ALL patient samples are known to present inactivating PTEN gene mutations. [1][2][3][4][5] PTEN mutation may collaborate with PTEN post-translational inactivation to maximize PTEN functional deficiency, thus contributing to increased PI3K/Akt activation and finally to leukemia resistance to chemotherapy. In fact, the occurrence of PTEN mutation/deletion is highly frequent in human T-ALL cell lines derived from relapsed patients.…”

“…Moreover, PTEN mutation was reported to occur in 2 of 35 relapsed T-ALL as a secondary event during disease progression. 3 As discussed below, the clinical relevance of PTEN mutations in pediatric T-ALL is available for only a limited number of patients 4,6 and should be analyzed with caution. Here, we report the prognostic impact of PTEN exon 7 mutations in a larger series of consecutive pediatric ALL patients treated in a single institution.…”