Attenuated cell cycle and DNA damage response transcriptome signatures and overrepresented cell adhesion processes imply accelerated progression in patients with lower‐risk myelodysplastic neoplasms

• Published in: International journal of cancer Vol. 154; no. 9; pp. 1652 - 1668
• Main Authors: Kaisrlikova, Monika, Kundrat, David, Koralkova, Pavla, Trsova, Iva, Lenertova, Zuzana, Votavova, Hana, Merkerova, Michaela Dostalova, Krejcik, Zdenek, Vesela, Jitka, Vostry, Martin, Simeckova, Radka, Markova, Marketa Stastna, Lauermannova, Marie, Jonasova, Anna, Cermak, Jaroslav, Divoky, Vladimir, Belickova, Monika
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.05.2024; Wiley Subscription Services, Inc
• Subjects: accelerated progression; Acute myeloid leukemia; Biomarkers; CD34 antigen; Cell Adhesion; Cell adhesion & migration; Cell Cycle; Cell differentiation; DNA damage; DNA Repair; Energy metabolism; Gene expression; Genes; Health risk assessment; Hematology; Humans; lower‐risk; MDS; Medical prognosis; Myelodysplastic syndrome; Myelodysplastic Syndromes - genetics; Neoplasms; NIMA-Related Kinases - genetics; NIMA-Related Kinases - metabolism; Progenitor cells; Prognosis; Risk assessment; Transcriptome; Transcriptomes; tumorigenesis barrier; Tumors; lower-risk; accelerated progression; MDS; transcriptome; tumorigenesis barrier
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.34834

Patients with myelodysplastic neoplasms (MDS) are classified according to the risk of acute myeloid leukemia transformation. Some lower‐risk MDS patients (LR‐MDS) progress rapidly despite expected good prognosis. Using diagnostic samples, we aimed to uncover the mechanisms of this accelerated progression at the transcriptome level. RNAseq was performed on CD34+ ribodepleted RNA samples from 53 LR‐MDS patients without accelerated progression (stMDS) and 8 who progressed within 20 months (prMDS); 845 genes were differentially expressed (ІlogFCІ > 1, FDR < 0.01) between these groups. stMDS CD34+ cells exhibited transcriptional signatures of actively cycling, megakaryocyte/erythrocyte lineage‐primed progenitors, with upregulation of cell cycle checkpoints and stress pathways, which presumably form a tumor‐suppressing barrier. Conversely, cell cycle, DNA damage response (DDR) and energy metabolism‐related pathways were downregulated in prMDS samples, whereas cell adhesion processes were upregulated. Also, prMDS samples showed high levels of aberrant splicing and global lncRNA expression that may contribute to the attenuation of DDR pathways. We observed overexpression of multiple oncogenes and diminished differentiation in prMDS; the expression of ZEB1 and NEK3, genes not previously associated with MDS prognosis, might serve as potential biomarkers for LR‐MDS progression. Our 19‐gene DDR signature showed a significant predictive power for LR‐MDS progression. In validation samples (stMDS = 3, prMDS = 4), the key markers and signatures retained their significance. Collectively, accelerated progression of LR‐MDS appears to be associated with transcriptome patterns of a quiescent‐like cell state, reduced lineage differentiation and suppressed DDR, inherent to CD34+ cells. The attenuation of DDR‐related gene‐expression signature may refine risk assessment in LR‐MDS patients. What's new? The mechanisms of transformation from myelodysplastic syndrome to acute myeloid leukemia are still unclear, with some lower‐risk MDS patients progressing rapidly despite a good prognosis. This comprehensive analysis of the CD34+ cell transcriptome identified several molecular signatures underlying accelerated progression in lower‐risk MDS patients. Early progression (within 20 months from diagnosis) appeared to be associated with decreased cell cycle and metabolic activity, downregulated DNA damage response and dysregulated cell adhesion gene expression. The suppression of CD34+ cell intrinsic DNA damage response seemed to be interconnected with decreased lineage differentiation, and may predict progression in patients with lower‐risk MDS.