Low PKCα expression within the MRD-HR stratum defines a new subgroup of childhood T-ALL with very poor outcome.

Oncotarget 2014 Jul 30

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Pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) outcome has improved in the last decades, yet one patient in every four still relapses. Except treatment response and immunophenotype, few markers are reliably prognostic in pediatric T-ALL patients. Aiming to improve T-ALL risk stratification, we investigated a new candidate biomarker with potential prognostic relevance. A phosphoproteomic screening of 98 pediatric T-ALL samples at diagnosis had been performed using the high-throughput Reverse Phase Protein Arrays technique, which led to the identification of PKCαS657 as an activated protein with a broad variation among T-ALL samples. To evaluate PKCα potential as a prognostic biomarker, PKCα expression was analyzed using RQ-PCR in a cohort of 173 patients, representative of ALL2000-ALLR2006 AIEOP study. A threshold of PKCα expression with the highest discrimination for incidence of relapse was identified. Patients with PKCα down-regulation, compared to patients with PKCα levels above the threshold, presented a markedly increased cumulative incidence of relapse (43.8% vs. 10.9%, P<0.001), as well as a worse 4-year overall survival (66% vs. 87.9%, P=0.002) and event-free survival (53.1% vs. 85.2%, P=0.002). In particular, low PKCα expression identified cases with extremely poor outcome within the high-risk minimal residual disease (MRD) stratum, their incidence of relapse being of 69% vs. 15% in the high PKCα levels group. In a multivariate analysis adjusting for main prognostic features, PKCα proved to be an independent prognostic factor related to incidence of relapse. Very high risk patients within the high-risk MRD stratum, identified by PKCα expression, could be proposed for experimental therapeutic protocols.

Citation

Gloria Milani, Paola Rebora, Benedetta Accordi, Luisa Galla, Silvia Bresolin, Gianni Cazzaniga, Barbara Buldini, Rossella Mura, Saverio Ladogana, Eugenia Giraldi, Valentino Conter, Geertruy Te Kronnie, Maria Grazia Valsecchi, Giuseppe Basso. Low PKCα expression within the MRD-HR stratum defines a new subgroup of childhood T-ALL with very poor outcome. Oncotarget. 2014 Jul 30;5(14):5234-45