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

Kontandreopoulou, Christina‐Nefeli; Diamantopoulos, Panagiotis; Giannopoulos, Andreas; Symeonidis, Argiris; Kotsianidis, Ιoannis; Pappa, Vasiliki; Galanopoulos, Athanasios; Panayiotidis, Panayiotis; Dimou, Maria; Solomou, Elena E.; Loupis, Theodoros; Zoi, Katerina; Giannakopoulou, Nefeli; Dryllis, Georgios; Hatzidavid, Sevastianos; Viniou, Nora‐Athina

doi:10.1080/10428194.2021.1998484

Cited by 4 publications

(3 citation statements)

References 37 publications

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“…In a recent study, it has been shown that the combined expression of small noncoding RNAs (sncRNAs) in MDS patients harboring SF3B1 and DNMT3A mutations can predict response to 5-AZA as well as define survival ( 143 ). Moreover, in a study of 98 MDS patients treated with 5-AZA, high methylation status of RNR subunit 1 ( RRM1 ) was observed in responders, thus making RNR a possible prognostic factor for response to 5-AZA and for predicting success of epigenetic treatment ( 144 ).…”

Section: Somatic Mutationsmentioning

confidence: 99%

The genetics of myelodysplastic syndromes and the opportunities for tailored treatments

Kontandreopoulou

Kalopisis²,

Viniou³

et al. 2022

Front. Oncol.

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Genomic instability, microenvironmental aberrations, and somatic mutations contribute to the phenotype of myelodysplastic syndrome and the risk for transformation to AML. Genes involved in RNA splicing, DNA methylation, histone modification, the cohesin complex, transcription, DNA damage response pathway, signal transduction and other pathways constitute recurrent mutational targets in MDS. RNA-splicing and DNA methylation mutations seem to occur early and are reported as driver mutations in over 50% of MDS patients. The improved understanding of the molecular landscape of MDS has led to better disease and risk classification, leading to novel therapeutic opportunities. Based on these findings, novel agents are currently under preclinical and clinical development and expected to improve the clinical outcome of patients with MDS in the upcoming years. This review provides a comprehensive update of the normal gene function as well as the impact of mutations in the pathogenesis, deregulation, diagnosis, and prognosis of MDS, focuses on the most recent advances of the genetic basis of myelodysplastic syndromes and their clinical relevance, and the latest targeted therapeutic approaches including investigational and approved agents for MDS.

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Section: Somatic Mutationsmentioning

confidence: 99%

The genetics of myelodysplastic syndromes and the opportunities for tailored treatments

Kontandreopoulou

Kalopisis²,

Viniou³

et al. 2022

Front. Oncol.

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“…Τhe relatively short-term duration of responses (18-20 months for patients with MDS [9]) and the inevitable development of resistance to HMAs have widely been reported. Thus, the identi cation of prognostic factors [10][11][12][13] and a deeper understanding of the underlying mechanisms, directing the development of response or resistance to HMAs are of substantial clinical importance.…”

Section: Introductionmentioning

confidence: 99%

Fetal hemoglobin induction in azacytidine responders enlightens methylation patterns related to blast clearance in higher-risk MDS and CMML

Chatzilygeroudi,

Chondrou,

Boers

et al. 2024

Preprint

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Background As new treatment options for patients with higher-risk myelodysplastic syndromes are emerging, identification of prognostic markers for hypomethylating agent (HMA) treatment and understanding mechanisms of their delayed and short-term responses are essential. Early fetal hemoglobin (HbF) induction has been suggested as a prognostic indicator for decitabine treated patients. Although epigenetic mechanisms are assumed, responding patients’ epigenomes have not been thoroughly examined. We aimed to clarify HbF kinetics and prognostic value for azacytidine treated patients, as well as the epigenetic landscape that might influence HbF re-expression and its clinical relevance. Results Serial HbF measurements by high performance liquid chromatography (n = 20) showed induction of HbF only among responders (p = 0.019). Moreover, HbF increase immediately after the first azacytidine cycle demonstrated prognostic value for progression free survival (PFS) (p = 0.032, HR = 0.19, CI:0.24–1.63). Changes in methylation patterns were revealed with methylated DNA genome-wide sequencing analysis (n = 7) for FOG-1, RCOR-1, ZBTB7A and genes of the NuRD complex components. Targeted pyrosequencing methodology (n = 28) revealed a strong inverse correlation between the degree of γ-globin gene (HBG2) promoter methylation and baseline HbF levels (p = 0.003, rs=-0.663). A potential epigenetic mechanism of HbF re-expression in azacytidine responders was enlightened by targeted methylation analysis, through hypomethylation of site − 53 of HBG2 promoter (p = 0.039, rs=-0.504), which corresponds to MBD2-NuRD binding site, and to hypermethylation of the CpG326 island of ZBTB7A (p = 0.05, rs=0.482), a known HbF repressor. These changes were associated to blast cell clearance (pHBG2=0.011, rs=0.480/ pZBTB7A=0.026, rs=0.427) and showed prognostic value for PFS (pZBTB7A=0.037, HR = 1.14, CI:0.34–3.8). Conclusions Early HbF induction is featured as an accessible prognostic indicator for HMA treatment and the proposed potential epigenetic mechanism of HbF re-expression in azacytidine responders includes hypomethylation of the γ-globin gene promoter region and hypermethylation of the CpG326 island of ZBTB7A. The association of these methylation patterns with blast clearance and their prognostic value for PFS paves the way to discuss in depth azacytidine epigenetic mechanism of action.

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“…The relatively short-term duration of responses (18–20 months for patients with MDS [ 9 ]) and the inevitable development of resistance to HMAs have widely been reported. Thus, the identification of prognostic factors [ 10 – 13 ] and a deeper understanding of the underlying mechanisms, directing the development of response or resistance to HMAs, are of substantial clinical importance.…”

Section: Introductionmentioning

confidence: 99%

Fetal hemoglobin induction in azacytidine responders enlightens methylation patterns related to blast clearance in higher-risk MDS and CMML

Chatzilygeroudi,

Chondrou,

Boers

et al. 2024

Clin Epigenet

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Background As new treatment options for patients with higher-risk myelodysplastic syndromes are emerging, identification of prognostic markers for hypomethylating agent (HMA) treatment and understanding mechanisms of their delayed and short-term responses are essential. Early fetal hemoglobin (HbF) induction has been suggested as a prognostic indicator for decitabine-treated patients. Although epigenetic mechanisms are assumed, responding patients’ epigenomes have not been thoroughly examined. We aimed to clarify HbF kinetics and prognostic value for azacytidine treated patients, as well as the epigenetic landscape that might influence HbF re-expression and its clinical relevance. Results Serial HbF measurements by high-performance liquid chromatography (n = 20) showed induction of HbF only among responders (p = 0.030). Moreover, HbF increase immediately after the first azacytidine cycle demonstrated prognostic value for progression-free survival (PFS) (p = 0.032, HR = 0.19, CI 0.24–1.63). Changes in methylation patterns were revealed with methylated DNA genome-wide sequencing analysis (n = 7) for FOG-1, RCOR-1, ZBTB7A and genes of the NuRD-complex components. Targeted pyrosequencing methodology (n = 28) revealed a strong inverse correlation between the degree of γ-globin gene (HBG2) promoter methylation and baseline HbF levels (p = 0.003, rs = − 0.663). A potential epigenetic mechanism of HbF re-expression in azacytidine responders was enlightened by targeted methylation analysis, through hypomethylation of site -53 of HBG2 promoter (p = 0.039, rs = − 0.504), which corresponds to MBD2-NuRD binding site, and to hypermethylation of the CpG326 island of ZBTB7A (p = 0.05, rs = 0.482), a known HbF repressor. These changes were associated to blast cell clearance (pHBG2 = 0.011, rs = 0.480/pZBTB7A = 0.026, rs = 0.427) and showed prognostic value for PFS (pZBTB7A = 0.037, HR = 1.14, CI 0.34–3.8). Conclusions Early HbF induction is featured as an accessible prognostic indicator for HMA treatment and the proposed potential epigenetic mechanism of HbF re-expression in azacytidine responders includes hypomethylation of the γ-globin gene promoter region and hypermethylation of the CpG326 island of ZBTB7A. The association of these methylation patterns with blast clearance and their prognostic value for PFS paves the way to discuss in-depth azacytidine epigenetic mechanism of action. Graphical abstract

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

Cited by 4 publications

References 37 publications

The genetics of myelodysplastic syndromes and the opportunities for tailored treatments

The genetics of myelodysplastic syndromes and the opportunities for tailored treatments

Fetal hemoglobin induction in azacytidine responders enlightens methylation patterns related to blast clearance in higher-risk MDS and CMML

Fetal hemoglobin induction in azacytidine responders enlightens methylation patterns related to blast clearance in higher-risk MDS and CMML

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