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


METHODS
We 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.


RESULTS
EZH2 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.


CONCLUSIONS
The 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.
Department of Woman, Child and General and Specialized Surgery, Pediatric Oncology Unit - Second University of Naples, Via Luigi De Crecchio 4, 80138, Naples, Italy. velia.dangelo@unina2.it.
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D'Angelo
Department of Woman, Child and General and Specialized Surgery, Pediatric Oncology Unit - Second University of Naples, Via Luigi De Crecchio 4, 80138, Naples, Italy. adriana.iannotta@unina2.it.
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Iannotta
Department of Woman, Child and General and Specialized Surgery, Pediatric Oncology Unit - Second University of Naples, Via Luigi De Crecchio 4, 80138, Naples, Italy. maria.ramaglia@unina2.it.
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Ramaglia
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Via S.M. Costantinopoli, 16, 80138, Naples, Italy. angela.lombardi@unina2.it.
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Lombardi
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Via S.M. Costantinopoli, 16, 80138, Naples, Italy. mayra.zarone@alice.it.
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Zarone
Department of Experimental Medicine, Section of Biotechnology and Medical Histology and Embryology, Second University of Naples, Naples, Italy. vincenzo.desiderio@unina2.it.
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Desiderio
Department of Woman, Child and General and Specialized Surgery, Pediatric Oncology Unit - Second University of Naples, Via Luigi De Crecchio 4, 80138, Naples, Italy. draffinita@gmail.com.
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Affinita
Department of Woman, Child and General and Specialized Surgery, Pediatric Oncology Unit - Second University of Naples, Via Luigi De Crecchio 4, 80138, Naples, Italy. drgiuliapecoraro@gmail.com.
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Pecoraro
Department of Woman, Child and General and Specialized Surgery, Pediatric Oncology Unit - Second University of Naples, Via Luigi De Crecchio 4, 80138, Naples, Italy. martinadimartino@libero.it.
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Di Martino
Department of Woman, Child and General and Specialized Surgery, Pediatric Oncology Unit - Second University of Naples, Via Luigi De Crecchio 4, 80138, Naples, Italy. paolo.indolfi@unina2.it.
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Indolfi
Department of Woman, Child and General and Specialized Surgery, Pediatric Oncology Unit - Second University of Naples, Via Luigi De Crecchio 4, 80138, Naples, Italy. fiorina.casale@unina2.it.
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Casale
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Via S.M. Costantinopoli, 16, 80138, Naples, Italy. michele.caraglia@unina2.it.
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Caraglia
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002648:Child; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D008297:Male; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000628:therapy*
C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2