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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. [ABSTRACT FROM AUTHOR]

Mutations in the splicing factor 3b subunit 1 (SF3B1) gene are frequent in myelodysplastic neoplasms (MDS). Because the splicing process is involved in the production of circular RNAs (circRNAs), we investigated the impact of SF3B1 mutations on circRNA processing. Using RNA sequencing, we measured circRNA expression in CD34+ bone marrow MDS cells. We defined circRNAs deregulated in a heterogeneous group of MDS patients and described increased circRNA formation in higher‐risk MDS. We showed that the presence of SF3B1 mutations did not affect the global production of circRNAs; however, deregulation of specific circRNAs was observed. Particularly, we demonstrated that strong upregulation of circRNAs processed from the zinc finger E‐box binding homeobox 1 (ZEB1) transcription factor; this upregulation was exclusive to SF3B1‐mutated patients and was not observed in those with mutations in other splicing factors or other recurrently mutated genes, or with other clinical variables. Furthermore, we focused on the most upregulated ZEB1‐circRNA, hsa_circ_0000228, and, by its knockdown, we demonstrated that its expression is related to mitochondrial activity. Using microRNA analyses, we proposed miR‐1248 as a direct target of hsa_circ_0000228. To conclude, we demonstrated that mutated SF3B1 leads to deregulation of ZEB1‐circRNAs, potentially contributing to the defects in mitochondrial metabolism observed in SF3B1‐mutated MDS. [ABSTRACT FROM AUTHOR]

Objectives Lenalidomide is a potent drug with pleiotropic effects in patients with myelodysplastic syndrome ( MDS) with deletion of the long arm of chromosome 5 [del(5q)]. We investigated its effect on regulation of micro RNA (mi RNA) expression profiles in del(5q) patients with MDS in vivo. Methods We used mi RNA expression microarrays to study changes in mi RNA levels in peripheral blood CD14+ monocytes collected from patients before and during lenalidomide treatment and compared them with those from healthy donors. Results Before treatment, we observed strong upregulation of pro-apoptotic miR-34a and miR-34a* that diminished during lenalidomide exposure. Upregulation of HOX-related miR-196b and erythroid-specific miR-451 seen in untreated patients remained unchanged after the treatment. At the time of hematologic response, expression of several mi RNAs clustering to the 14q32 locus was reduced. Additionally, we focused more deeply on mi RNAs from the 5q commonly deleted region and found that levels of miR-378 and miR-378* followed haploinsufficiency trend. Conclusions This report describes changes in mi RNA expression in del(5q) patients with MDS treated with lenalidomide, likely arising from deregulation of pathways implicated in lenalidomide action. [ABSTRACT FROM AUTHOR]