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

• Published in: Oncotarget Vol. 5; no. 14; pp. 5234 - 5245
• Main Authors: Milani, Gloria, Rebora, Paola, Accordi, Benedetta, Galla, Luisa, Bresolin, Silvia, Cazzaniga, Gianni, Buldini, Barbara, Mura, Rossella, Ladogana, Saverio, Giraldi, Eugenia, Conter, Valentino, Te Kronnie, Geertruy, Valsecchi, Maria Grazia, Basso, Giuseppe
• Format: Journal Article
• Language: English
• Published: United States 30-07-2014
• Subjects: Adolescent; Biomarkers, Tumor - genetics; Child; Child, Preschool; Female; Humans; Infant; Male; Neoplasm, Residual; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - enzymology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Prognosis; Protein Kinase C-alpha - biosynthesis; Protein Kinase C-alpha - genetics; Protein Kinase C-alpha - metabolism; Risk Factors; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Signal Transduction; Survival Rate; Treatment Outcome
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.2062

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.