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.

Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium

“…Although loss of PKCα mRNA and protein has been noted in other tumor types, such as colon cancer (Verstovsek et al, 1998), non-small cell lung cancer (Hill et al, 2014), basal cell carcinoma (Neill et al, 2003), and T cell acute lymphoblastic leukemia (T-ALL) (Milani et al, 2014), the mechanisms underlying PKCα deficiency have yet to be defined. Our qRT-PCR and IHC analysis argues that decreased mRNA expression is the major mechanism involved in disabling PKCα functions in the endometrium.…”

“…Genetic deletion of PKCα led to increased tumor burden, adenoma-to-carcinoma progression, and reduced survival in the APC Min/+ mouse model of intestinal neoplasia (Oster and Leitges, 2006) and KRas-mediated models of lung tumorigenesis (Hill et al, 2014). Low PKCα expression identified a new subgroup of childhood T-ALL with an extremely poor outcome (Milani et al, 2014) and appears to enhance the tumorigenic potential of Gli1 in basal cell carcinoma (Neill et al, 2003). It will be interesting to determine if common mechanisms mediate PKCα loss in these tumor types.…”

Protein kinase C: perfectly balanced

“…Indeed, analysis of clinical data support this possibility. Low levels of PKCα expression (both mRNA and protein) have recently been shown to predict poor outcome in T-cell Acute Lymphoblastic Leukemia (T-ALL) (Milani et al 2014). Similarly, low levels of PKCβII protein predict poor outcome in colorectal cancer (Dowling et al 2016).…”

Reversing the Paradigm: Protein Kinase C as a Tumor Suppressor

“…Low levels of PKCα expression have recently been shown to predict poor outcome in T-cell Acute Lymphoblastic Leukemia (T-ALL) [33]. Similarly, low levels of PKCβII protein predict poor outcome in colorectal cancer [34].…”