EZH2 is increased in paediatric T-cell acute lymphoblastic leukemia and is a suitable molecular target in combination treatment approaches

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.

Long noncoding RNA XIST promotes malignancies of esophageal squamous cell carcinoma via regulation of miR-101/EZH2

“…EZH2 constitutes the main component of PRC2 as a transcriptional repressor [ 34 ] and dysregulation of EZH2 is implicated in progression of many types of human cancers [ 35 , 36 ] including ESCC [ 28 ]. Studies also confirmed the post-transcriptional regulation mechanisms underlying EZH2 expression [ 26 , 37 ] and these include miR-101 in gastric [ 20 ], hepatocellular [ 27 ] and esophageal cancer [ 25 ].…”

EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications

“…In NKTL, selective JAK3 inhibitor PF-956980 removes EZH2-Y244 phosphorylation and thus obliterates oncogenic and downstream activating function of EZH2 [69]. MELK inhibition in this malignancy DZnep and JQ1 BL, MCL, GC-DLBCL Zhao X., et al [51] DZnep and Daunoblastine T-ALL D'Angelo V., et al [156] UNC1999 and Bortezomib/Carfilzomib MM Rizq O., et al [154] DZnep and Vorinostat MCL, BL Zhang X., et al [54] GSK126/Dznep and ACY-957/1044 EZH2-mutant GC-DLBCL Johnson DP., et al [160] Abbreviations: GC-DLBCL germinal center diffuse large B cell lymphoma, DLBCL diffuse large B cell lymphoma; T-ALL T cell acute lymphoblastic leukemia, MCL mantel cell lymphoma, MM multiple myeloma, BL Burkitt lymphoma effectively diminishes EZH2 level by eliminating EZH2 S220 phosphorylation and promoting associated K222 ubiquitination [58].…”

“…In recent years, therapeutics combining individual EZH2 inhibitor with other drugs have been explored. Synergistic or re-sensitizing effects between EZH2 inhibitors and traditional cytotoxic anti-cancer drugs have been seen [155,156]. In view of the abundantly present epigenetic abnormalities of H3K27 tri-methylation and histone acetylation, a couple of studies have combined EZH2 inhibitors with different HDAC inhibitors for the treatment in MM [157,158] and B cell lymphoma cells [54,123,159,160], and favorable therapeutic coordination were observed.…”

Solanine induced apoptosis and increased chemosensitivity to Adriamycin in T-cell acute lymphoblastic leukemia cells

“…T-ALL accounts for 10-15% of pediatric and 25% of adult ALL cases (2,3). The age of the patient at diagnosis, leukocyte count, ethnicity, gender and immunophenotype are clinical prognostic parameters that classify ALL patients into different risk groups (4).…”

“…The prognosis of T-ALL has improved with the development of high-dose multi-agent chemotherapy, with a cure rate of ~85% in children and ~50% in adults (5). However, the treatment is often accompanied by severe acute toxicities and side effects, such as primary resistance, early relapse and secondary tumors (2,3). The identification of new agents for T-ALL patients is urgently required.…”