Myelodysplastic Neoplasm (MDS) is a heterogeneous group of clonal hematopoietic stem cell diseases. MDS is characterized by the presence of bone marrow (BM) dysplasias, peripheral blood cytopenias and is frequently associated with progression to Acute Myeloid Leukemia (AML). MDS represents an ideal model to study the steps involved in leukemogenesis. Recent advances at the molecular level have provided new insights into the development of MDS and its progression to AML. The Enhancer of Zeste Homolog 2 (EZH2) is a histone methyltransferase. It is the catalytic subunit of PCR2 for tri-methylation of histone 3 at lysine 27 (H3K27me) by SET domain in its C-terminus, which silences target genes involved in various biological functions as cell cycle, cell proliferation and differentiation. PcG proteins are important epigenetic regulators and critical factors of pluripotency and differentiation of stem cells as well as aberrant gene expression during the malignant transformation. Few studies have investigated the expression of EZH2 in MDS and the results are controversial.

To analyze the expression pattern of the EZH2 gene in adult patients with MDS and its association with karyotype and progression to AML.

This study included 70 adult patients with MDS and 20 adult donors of bone marrow for hematopoietic stem cell transplantation (HSCT). Cytogenetic analyses were performed by G-banding and fluorescence in situ hybridization (FISH). Analysis of the expression pattern of the EZH2 gene was performed by real-time PCR.

Analysis of the relative expression levels of the EZH2 gene showed that patients had a higher expression when compared to controls (p < 0.0005). Abnormal karyotypes were observed in 49% of the cases analyzed (34/70). The association of relative expression levels of EZH2 between patients with normal karyotypes and abnormal karyotypes showed a higher relative expression. of EZH2 in patients with abnormal karyotypes (p < 0.002). Disease progression was observed in 44% of the patients (31/70). The patients who had leukemic evolution presented a relative expression pattern of EZH2 significantly higher compared to patients without progression (p < 0.0001).

Few studies have evaluated EZH2 expression in adult patients with MDS. However, these studies show controversial results. One study showed that EZH2 overexpression is associated with poor prognosis. While the other showed that the low EZH2 expression is associated with alterations in chromosome 7 and disease progression. In our study, we observed that the EZH2 overexpression in adult patients with MDS was associated with abnormal karyotipes and leukemic evolution.

Our study suggests that EZH2 overexpression is associated with the evolution from MDS to AML, being a possible prognostic biomarker.

Ministério da Saúde – INCA.