Oncotarget

Clinical Research Papers:

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

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 and Giuseppe Basso

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Oncotarget. 2014; 5:5234-5245. https://doi.org/10.18632/oncotarget.2062

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Abstract

Gloria Milani1, Paola Rebora2, Benedetta Accordi1, Luisa Galla1, Silvia Bresolin1, Gianni Cazzaniga3, Barbara Buldini1, Rossella Mura4, Saverio Ladogana5, Eugenia Giraldi6, Valentino Conter7, Geertruy Te Kronnie1, Maria Grazia Valsecchi2 and Giuseppe Basso1

1 Laboratory of Oncohematology, Department of Women’s and Children’s Health, University of Padova, Italy

2 Center of Biostatistics for Clinical Epidemiology, Department of Health Sciences, University of Milano-Bicocca, Monza, Italy

3 Centro Ricerca Tettamanti, University of Milano-Bicocca, Ospedale San Gerardo, Monza, Italy

4 Oncoematologia Pediatrica e Patologia della Coagulazione, Ospedale Regionale per le Microcitemie, Cagliari, Italy

5 Oncoematologia Pediatrica, Ospedale “Casa Solievo della Sofferenza”, San Giovanni Rotondo, Italy

6 U.O. Pediatria, Ospedale Papa Giovanni XXIII, Bergamo, Italy

7 Pediatric Department, University of Milano-Bicocca, Ospedale San Gerardo, Monza, Italy

Correspondence:

Geertruy te Kronnie, email:

Keywords: Low PKCα expression, Childhood T-cell Acute Lymphoblastic Leukemia, T-ALL prognostic marker

Received: April 8, 2014 Accepted: June 5, 2014 Published: June 6, 2014

Abstract

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.


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