Abstract
BackgroundT-cell Acute Lymphoblastic Leukemia (ALL) represents about 10–15 % of pediatric ALL cases. EZH2, one of the components of Polycomb group proteins (PRC2) complex, catalyzes the trimethylation of histone H3 lysine 27 that is associated with transcriptional repression and tumor development.MethodsWe examined the expression levels of PRC2 complex in primary samples of T cells ALL at diagnosis by western blotting and real time PCR. We evaluated the effect of 3-deazaneplanocin-A (DZNep), an EZH2 inhibitor, alone and in combination with Daunoblastine on cell viability, apoptotic death and cell cycle distribution of T cell established Jurkat cell line.ResultsEZH2 was expressed in 75 % samples at different extents mainly with high expression level. SUZ12 was expressed in 60 % samples and EED in all samples, respectively. The Kaplan-Meier analysis shows that T-ALL expressing EZH2 had a lower probability of disease-free survival (DFS) compared to T-ALL negative for EZH2 (23 % vs 100 %) (p = 0.01). The EZH2 inhibitor DZNep used in combination with Daunoblastine was synergistic in inducing growth inhibition and increasing the apoptosis in T-ALL Jurkat cells at 48 and 72 h paralleled by EZH2 decreased expression. Moreover, the combination decreased the activity of Erk-1/2 proliferation enzymes with no effects on Akt survival pathway.ConclusionsThe evaluation of EZH2 expression in pediatric T-ALL can be useful in predict the clinical outcome of the patients and EZH2 can be a useful target to improve the efficacy of conventional chemotherapy in this subset of patients with bad prognosis.
Highlights
T-cell Acute Lymphoblastic Leukemia (ALL) represents about 10–15 % of pediatric ALL cases
Epigenetic alterations have an important role in leukemogenesis and Polycomb group proteins, which consist of two complexes (PRC1 and PRC2), represent a major class of epigenetic regulators in development and transcriptional repression
Fourteen patients (77.8 %) had white blood cells (WBC) higher than 20,000/mmc and six (22.2 %) a lower count (Table 2). They were subdivided into three risk categories, according to their prognostic parameters: standard risk (SR) if a white cell count below 20,000/mmc, DNA index between 1.16 and 1.60, good response to prednisone treatment, no translocation t (9;22) or t (4;11), complete remission at the conclusion of induction therapy; high risk (HR) if negative response to prednisone, evidence of translocation t(9;22) o t(4;11), not in remission at the conclusion of induction therapy, and Intermediate risk (IR) whose characteristics did not fall into either of the previous two categories
Summary
T-cell Acute Lymphoblastic Leukemia (ALL) represents about 10–15 % of pediatric ALL cases. EZH2, one of the components of Polycomb group proteins (PRC2) complex, catalyzes the trimethylation of histone H3 lysine 27 that is associated with transcriptional repression and tumor development. PRC2 controls the pivotal methylation of lysine 27 of histone H3 (H3K27) catalyzed by the SETdomain containing enhancer of zest homolog 2 (EZH2) protein and its cofactors [1]. Deregulation of this histone modification can lead to epigenetic silencing of genes that promote differentiation and leads to leukemogenesis [2]. Components of PRC2 are required for embryonic development and notably loss of EZH2 gene is associated with a block in B- and T-cell differentiation.
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