Distinct mutation features and its clinical significance in myelodysplastic syndromes with normal karyotype.

Myelodysplastic syndromes (MDS) is a highly heterogeneous myeloid neoplastic disease, which needs personalized evaluation and therapy. To analyze the features and significance of gene mutations for MDS patients with normal karyotype (NK) at diagnosis, targeted sequencing was conducted on 616 MDS patients with NK, alongside 457 MDS cases with abnormal karyotype (AK). The results showed that the incidence of somatic mutation reached 70.3% and 83.8% in the NK and AK group, respectively. Initial mutation including ASXL1, DNMT3A and TET2 were common in NK group, which is the same as AK group. Some karyotype-associated gene mutations, such as TP53 and U2AF1, were relatively rare in NK group. Moreover, 34 out of 91 samples who progressed to acute myeloid leukemia (AML) underwent repeat sequencing during follow-up. 25 cases were checked out with newly emerged mutations. The AML-associated genetic alterations mainly involved with active signaling and transcription factors. In patients with NK, serial targeted sequencing was employed for minimal residual disease (MRD) monitoring, indicating the efficacy and relapse of the patients. In summary, MDS with NK showed distinct mutation features from those with AK. High-frequency gene mutations together with the mutational evolution suggested the diagnostic and monitoring significance of next generation sequencing for NK-MDS.

DHX9-mediated pathway contributes to the malignant phenotype of myelodysplastic syndromes.

DHX9 is a member of the DEAH (Asp-Glu-Ala-His) helicase family and regulates DNA replication and RNA processing. DHX9 dysfunction promotes tumorigenesis in several solid cancers. However, the role of DHX9 in MDS is still unknown. Here, we analyzed the expression of DHX9 and its clinical significance in 120 MDS patients and 42 non-MDS controls. Lentivirus-mediated DHX9-knockdown experiments were performed to investigate its biological function. We also performed cell functional assays, gene microarray, and pharmacological intervention to investigate the mechanistic involvement of DHX9. We found that overexpression of DHX9 is frequent in MDS and associated with poor survival and high risk of acute myeloid leukemia (AML) transformation. DHX9 is essential for the maintenance of malignant proliferation of leukemia cells, and DHX9 suppression increases cell apoptosis and causes hypersensitivity to chemotherapeutic agents. Besides, knockdown of DHX9 inactivates the PI3K-AKT and ATR-Chk1 signaling, promotes R-loop accumulation, and R-loop-mediated DNA damage.

Decreased FOXO1 Expression Is Correlated with Poor Prognosis in Myelodysplastic Syndromes.

Myelodysplastic syndrome is one of the main hematological malignancies that threaten the health of the elderly. However, biomarkers which predict the progression and prognosis of MDS are still controversial and puzzling. FOXO1 gene plays an important role in a variety of intracellular functions, including tumor suppression and cellular immune regulation. However, there is no research report on the correlation between FOXO1 and the clinical features of MDS including immune environment. In this study, we observed that FOXO1 expression is associated with neutrophil count, blasts, chromosome and different MDS scoring systems. FOXO1 expression is closely related to MDS cell immune polarization, and the increase expression of FOXO1 is significantly related to the amplification of immune cell polarization ratio. In addition, FOXO1 expression is associated with progression-free survival and overall survival in MDS patients. Moreover, in a multivariate model FOXO1 low-expression was an independent predictor of poor survival in MDS. In summary, FOXO1 may play a candidate tumor suppressor in MDS, and FOXO1 is a useful independent prognostic predictor in MDS, and it may provide a candidate target therapy in future.