Abstract
Abstract 4118
Introduction:
The polycomb repressive complex (PRC) 2 contains 3 core proteins, EZH2 (enhancer of zeste homolog 2), SUZ12, and EED, in which the SET (suppressor of vaegation-enhancer of zeste-trithorax) domain of EZH2 mediates the histone methyltransferase activity. This induces trimethylation of lysine 27 on histone H3, regulates the expression of HOX genes, and promotes proliferation and aggressiveness of neoplastic cells. EZH2, a known repressor of gene transcription, has been reported to be overexpressed in many cancers and correlates with poor prognosis. EZH2 may also be involved in disease progression in patients with the classical Philadelphia-negative chronic myeloproliferative neoplasms (CMPNs) encompassing essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Since the potential oncogenic role of EZH2 in CMPNs has never been investigated, we have assessed gene expression of EZH2 in a cohort of patients with CMPNs.
Patients and Methods:
Using Affymetrix HG-U133 2.0 Plus microarrays, recognizing 54675 probe sets (38500 genes), gene expression profiling has been performed on control subjects (n=21) and patients with ET (n =19), PV (n=41), and PMF (n=9). All patients were diagnosed according to the WHO criteria of a CMPN. Total RNA was purified from whole blood and amplified to biotin-labeled RNA and hybridized to microarray chips.
Results:
We identified 20439, 25307, 17417, and 25421 probe sets which were differentially expressed between controls and patients with ET, PV, PMF, and CPMNs as a whole, respectively (false discovery rate (FDR) adjusted p values < 0.05). These genes included EZH2, which was highly significantly upregulated in patients with PMF as compared to controls (2.3 fold upregulated; uncorrected p-value=1.09×10-8 and FDR=1.75×10-6, and between PMF and non-PMF patients (fold change=2.0, FDR < 0.0005). No significant differences in EZH2 gene expression were recorded between controls and ET patients, controls and PV patients, or controls and the CMPN group as a whole. Within patients, the EZH2 gene was also differentially expressed with the highest levels being recorded in patients with PMF compared to PV patients (fold change=2.4, FDR < 7.5 ×10-6).
Discussion and Conclusions:
Using global gene expression profiling we have found the EZH2 gene to be significantly upregulated in CMPN patients, with the highest expression levels being found in PMF. We hypothesize that an altered expression of EZH2 may be involved in the transformation of ET and PV into myelofibrosis. It remains to be clarified if deregulation of EZH2 occurs consequent to mutations in the EZH2-gene. Enhanced EZH2 expression may also be associated with silencing of differentiation genes during myelofibrotic and leukemic transformation. An increased expression of EZH2 may provide a proliferative advantage of the malignant clone through interaction with the pathways of key elements controlling cell growth arrest and differentiation, (e.g. nuclear factor kappa beta and - the proteasome pathway). Studies are in progress to elucidate if genomic loss of distinct microRNAs (microRNA 101 leads to overexpression of EZH2 in cancer is associated with overexpression of EZH2 in CMPNs. Highly expressed EZH2 may be a new marker of an aggressive clinical phenotype which might imply EZH2 as a novel biomarker for predicting prognosis. If so, EZH2-blockade might be a novel approach to be incorporated in the strategies for developing epigenetic therapies in patients with CMPNs.
Disclosures:
No relevant conflicts of interest to declare.
Gene Expression Profiling and Cellular Distribution of Molecules with Altered Expression in the Hippocampal CA1 Region after Developmental Exposure to Anti-Thyroid Agents in Rats