Bone marrow ribonucleotide reductase mRNA levels and methylation status as prognostic factors in patients with myelodysplastic syndrome treated with 5-Azacytidine
Christina‐Nefeli Kontandreopoulou, Panagiotis Diamantopoulos, Andreas Giannopoulos, Argiris Symeonidis, Ιoannis Kotsianidis, Vasiliki Pappa, Athanasios Galanopoulos, Panayiotis Panayiotidis, Maria Dimou, Elena E. Solomou, Theodoros Loupis, Katerina Zoi, Nefeli Giannakopoulou, Georgios Dryllis, Sevastianos Hatzidavid, Nora‐Athina Viniou, On behalf of the Hellenic MDS study Group
Abstract
Ribonucleotide Reductase (RNR) is a two-subunit (RRM1, RRM2) enzyme, responsible for the conversion of ribonucleotides to deoxyribonucleotides required for DNA replication. To evaluate RNR as a biomarker of response to 5-azacytidine, we measured RNR mRNA levels by a quantitative real-time PCR in bone marrow samples of 98 patients with myelodysplastic syndrome (MDS) treated with 5-azacytidine with parallel quantification of the gene promoter’s methylation. Patients with low RRM1 levels had a high RRM1 methylation status (p = 0.005) and a better response to treatment with 5-azacytidine (p = 0.019). A next-generation sequencing for genes of interest in MDS was also carried out in a subset of 61 samples. Splicing factor mutations were correlated with lower RRM1 mRNA levels (p = 0.044). Our results suggest that the expression of RNR is correlated with clinical outcomes, thus its expression could be used as a prognostic factor for response to 5-azacytidine and a possible therapeutic target in MDS.