PTEN/AKT Pathway Mutations Are Reciprocal to NOTCH-Activating Mutations In Pediatric T-Cell Acute Lymphoblastic Lymphoma (T-ALL)

Abstract 1710

Mutations in the PI3K/AKT pathway are often found in T-cell Acute Lymphoblastic Leukemia (T-ALL). To investigate the incidence of the PTEN/AKT aberrations in pediatric T-ALL, we retrospectively determined the incidence of PTEN, PI3K and AKT mutations in 142 pediatric T-ALL patients treated according to the Dutch DCOG or German COALL protocols.

Using PCR-sequencing and/or array-CGH, PTEN mutations/deletions were detected in 13% of the patients. Another 2% of the patients carried an AKT mutation, whereas none had mutations in PI3K. Using reverse-phase protein microarray analysis (RPMA), we demonstrated that PTEN protein expression was absent in PTEN-mutated or PTEN-deleted patients, with the exception of one patient that carried a PTEN missense mutation. We also identified several T-ALL cases that lacked PTEN protein expression, while we did not find evidence for PTEN mutations nor for differential PTEN promoter hypermethylation in these patients. PTEN or AKT mutations (PTEN/AKT) were especially observed in the TAL/LMO subgroup (p=0.001), but not in TLX3-rearranged cases (p=0.03). PTEN/AKT mutations nearly follows a pattern that seems reciprocal to the presence of NOTCH-activating mutations, indicating that PTEN/AKT mutations are not simply secondary events following NOTCH1/FBXW7 mutations such as initially suggested¹. Based on RPMA results, PTEN/AKT patients expressed significantly lower levels of NOTCH1 protein compared to these of other patients samples and also had the lowest expression of MYC, a direct NOTCH1 target. This might explain γ-secretase inhibitor insensitivity of PTEN-mutated cases, in stead of acquired resistance as a consequence of oncogenic addiction switch¹. Survival rates for PTEN/AKT patients seemed comparable to wild-type patients (5-yrs DFS DCOG WT 71±6% vs PTEN/AKT 60±16%, COALL WT 78±6% vs PTEN/AKT 57±15%). However, when NOTCH1/FBXW7-mutated patients were separated from the wild-type group, the presence for NOTCH1/FBXW7 or PTEN/AKT mutations was associated with poor outcome, whereas the disease-free survival rate for wild-type patients was nearly 100% (5-yrs DFS DCOG+COALL WT 92±6% vs PTEN/AKT/NOTCH1 65±5%, p=0.005).

Taken together, almost 20% of pediatric T-ALL patients treated according to these protocols have loss-of-function PTEN or activating AKT mutations. PTEN or AKT mutations are especially identified in the TAL/LMO subgroup suggesting that these mutations act in concert with TAL1 and/or LMO2 for pathogenesis. PTEN/AKT mutations are identified in a reciprocal pattern with NOTCH1-activating mutations, suggesting that PTEN/AKT and NOTCH1-activating mutations have different effects in pathogenesis. Patients lacking PTEN/AKT and NOTCH1/FBXW7 mutations were associated with excellent outcome.

1 Palomero, T. et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med13, 1203–1210, doi:nm1636 [pii], 10.1038/nm1636 (2007).