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

Leuk Lymphoma. 2022 Mar;63(3):729-737. doi: 10.1080/10428194.2021.1998484. Epub 2021 Nov 5.

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.

Keywords: 5-azacytidine; Ribonucleotide reductase (RNR); methylation; myelodysplastic syndrome; response to treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azacitidine / pharmacology
  • Azacitidine / therapeutic use
  • Bone Marrow / metabolism
  • Humans
  • Methylation
  • Myelodysplastic Syndromes* / diagnosis
  • Myelodysplastic Syndromes* / drug therapy
  • Myelodysplastic Syndromes* / genetics
  • Prognosis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Ribonucleoside Diphosphate Reductase / genetics
  • Ribonucleoside Diphosphate Reductase / metabolism
  • Ribonucleotide Reductases* / genetics

Substances

  • RNA, Messenger
  • Ribonucleotide Reductases
  • Ribonucleoside Diphosphate Reductase
  • Azacitidine