title: Low PKCα expression within the MRD-HR stratum defines a new subgroup of childhood T-ALL with very poor outcome.
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.
authors.affiliation: Laboratory of Oncohematology, Department of Women's and Children's Health, University of Padova, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Milani
authors.affiliation: Center of Biostatistics for Clinical Epidemiology, Department of Health Sciences, University of Milano-Bicocca, Monza, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rebora
authors.affiliation: Laboratory of Oncohematology, Department of Women's and Children's Health, University of Padova, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Accordi
authors.affiliation: Laboratory of Oncohematology, Department of Women's and Children's Health, University of Padova, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Galla
authors.affiliation: Laboratory of Oncohematology, Department of Women's and Children's Health, University of Padova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bresolin
authors.affiliation: Centro Ricerca Tettamanti, University of Milano-Bicocca, Ospedale San Gerardo, Monza, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Cazzaniga
authors.affiliation: Laboratory of Oncohematology, Department of Women's and Children's Health, University of Padova, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Buldini
authors.affiliation: Oncoematologia Pediatrica e Patologia della Coagulazione, Ospedale Regionale per le Microcitemie, Cagliari, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Mura
authors.affiliation: Oncoematologia Pediatrica, Ospedale "Casa Solievo della Sofferenza", San Giovanni Rotondo, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Ladogana
authors.affiliation: U.O. Pediatria, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Giraldi
authors.affiliation: Pediatric Department, University of Milano-Bicocca, Ospedale San Gerardo, Monza, Italy.
authors.forename: Valentino
authors.initials: V
authors.lastname: Conter
authors.affiliation: Laboratory of Oncohematology, Department of Women's and Children's Health, University of Padova, Italy.
authors.forename: Geertruy
authors.initials: G
authors.lastname: Te Kronnie
authors.affiliation: Center of Biostatistics for Clinical Epidemiology, Department of Health Sciences, University of Milano-Bicocca, Monza, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Valsecchi
authors.affiliation: Laboratory of Oncohematology, Department of Women's and Children's Health, University of Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D018365:Neoplasm, Residual; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology* / Q000235:genetics; D011379:Prognosis; D051571:Protein Kinase C-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012307:Risk Factors; D015398:Signal Transduction; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha