Bone marrow ribonucleotide reductase mRNA levels and methylation status
as prognostic factors in patients with myelodysplastic syndrome treated
with 5-Azacytidine
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