Abstract
Although probability of event-free survival in pediatric lymphoblastic T-cell lymphoma (T-LBL) is about 75%, survival in relapsed patients is very poor, so the identification of new molecular markers is crucial for treatment optimization. Here, we demonstrated that the over-expression of miR-223 promotes tumor T-LBL cell growth, migration and invasion in vitro. We found out that SIK1, an anti-metastatic protein, is a direct target of miR-223 and consequently is significantly reduced in miR-223-overexpressing tumor cells. We measured miR-223 expression levels at diagnosis in tumor biopsies from 67 T-LBL pediatric patients for whom complete clinical and follow up data were available, and we found that high miR-223 expression (above the median value) is associated with worse prognosis (PFS 66% vs 94%, P=0.0036). In addition, the multivariate analysis, conducted taking into account miR-223 expression level and other molecular and clinical characteristics, showed that only high level of miR-223 is an independent factor for worse prognosis. MiR-223 represents a promising marker for treatment stratification in pediatric patients with T-LBL and we provide the first evidence of miR-223 potential role as oncomir by SIK1 repression.
Highlights
Childhood Lymphoblastic T-cell Lymphoma (T-LBL) represents about one-third of pediatric nonHodgkin lymphomas (NHLs), and it originates from lymphoid progenitor cells arrested at early stages of T-cell maturation [1]
The main clinical characteristics of the 67 patients with T-cell lymphoblastic lymphoma (T-LBL) are listed in Table 1, along with the univariate and multivariate analyses to account for the variables of gender, stage of disease, age at diagnosis, Central Nervous System (CNS) involvement, bone marrow involvement, mediastinal involvement, in addition to NOTCH1 mutational status and miR-223 expression level
We report that expression levels of miR-223 constitute a strong prognostic factor in pediatric T-LBL patients homogeneously treated according to BFM-type strategy
Summary
Childhood Lymphoblastic T-cell Lymphoma (T-LBL) represents about one-third of pediatric nonHodgkin lymphomas (NHLs), and it originates from lymphoid progenitor cells arrested at early stages of T-cell maturation [1]. 3 molecular markers have been reported in literature, which might be of prognostic relevance for pediatric T-LBL patients treated on BFM (Berlin-Munster-Frankfurt) based regimens: aberrations in chromosome 6q14-24, mutations of NOTCH1 and/or FBXW7 and mutations of PTEN [4]. Hotspot mutations in NOTCH1 and/or FBXW7 are observed in about 50% of pediatric T-ALL patients and reported to be associated with an improved treatment response or outcome [5, 6]. Similar data were reported for pediatric patients with T-ALL treated according to the ALL-BFM protocol [9, 10], a comparable regimen to that of NHL-BFM group administered to T-LBL patients, suggesting that NOTCH1 mutations might serve as a positive prognostic marker in the context of BFM-type treatment
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