Patients with lower-risk myelodysplastic syndromes (LR-MDS) have a generally favorable prognosis; however, a small proportion of cases progress rapidly. This study aimed to define molecular biomarkers predictive of LR-MDS progression and to uncover cellular pathways contributing to malignant transformation. The mutational landscape was analyzed in 214 LR-MDS patients, and at least one mutation was detected in 137 patients (64%). Mutated RUNX1 was identified as the main molecular predictor of rapid progression by statistics and machine learning. To study the effect of mutated RUNX1 on pathway regulation, the expression profiles of CD34 + cells from LR-MDS patients with RUNX1 mutations were compared to those from patients without RUNX1 mutations. The data suggest that RUNX1-unmutated LR-MDS cells are protected by DNA damage response (DDR) mechanisms and cellular senescence as an antitumor cellular barrier, while RUNX1 mutations may be one of the triggers of malignant transformation. Dysregulated DDR and cellular senescence were also observed at the functional level by detecting γH2AX expression and β-galactosidase activity. Notably, the expression profiles of RUNX1-mutated LR-MDS resembled those of higher-risk MDS at diagnosis. This study demonstrates that incorporating molecular data improves LR-MDS risk stratification and that mutated RUNX1 is associated with a suppressed defense against LR-MDS progression.

• MeSH
• Leukemia, Myeloid, Acute * genetics   MeSH
• Humans MeSH
• Mutation MeSH
• Myelodysplastic Syndromes * pathology   MeSH
• Cell Transformation, Neoplastic genetics   metabolism   MeSH
• Prognosis MeSH
• Core Binding Factor Alpha 2 Subunit genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Core Binding Factor Alpha 2 Subunit MeSH
• RUNX1 protein, human MeSH Browser

BACKGROUND/AIM: Prediction of response to azacitidine (AZA) treatment is an important challenge in hematooncology. In addition to protein coding genes (PCGs), AZA efficiency is influenced by various noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs), circular RNAs (circRNAs), and transposable elements (TEs). MATERIALS AND METHODS: RNA sequencing was performed in patients with myelodysplastic syndromes or acute myeloid leukemia before AZA treatment to assess contribution of ncRNAs to AZA mechanisms and propose novel disease prediction biomarkers. RESULTS: Our analyses showed that lncRNAs had the strongest predictive potential. The combined set of the best predictors included 14 lncRNAs, and only four PCGs, one circRNA, and no TEs. Epigenetic regulation and recombinational repair were suggested as crucial for AZA response, and network modeling defined three deregulated lncRNAs (CTC-482H14.5, RP11-419K12.2, and RP11-736I24.4) associated with these processes. CONCLUSION: The expression of various ncRNAs can influence the effect of AZA and new ncRNA-based predictive biomarkers can be defined.

• Keywords
• Noncoding RNAs, acute myeloid leukemia, azacytidine, circular RNAs, myelodysplastic syndrome, transposable elements,
• MeSH
• Leukemia, Myeloid, Acute * drug therapy   genetics   MeSH
• Azacitidine pharmacology   therapeutic use   MeSH
• Epigenesis, Genetic MeSH
• Humans MeSH
• Myelodysplastic Syndromes * drug therapy   genetics   MeSH
• RNA, Long Noncoding * genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Azacitidine MeSH
• RNA, Long Noncoding * MeSH