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(C and D) PFS and OS of patients with increased mean ctDNA VAF versus patients with no increased mean ctDNA VAF based on pre- and post-treatment ctDNA change, respectively. Twenty-seven patients had pre- and post-treatment plasma-derived ctDNA, and paired baseline BM DNA NGS assessments were included for both concordance analysis and dynamic ctDNA analysis. Three patients with only pre- and post-treatment ctDNA assessments and one patient with only post-treatment ctDNA assessments were used for dynamic ctDNA analysis (Figure 1). [Extracted from the article]

Background: Myelodysplastic syndrome (MDS) arises from a rare population of aberrant hematopoietic stem and progenitor cells (HSPCs). These cells are relatively quiescent and therefore treatment resistant. Understanding mechanisms underlying their maintenance is critical for effective MDS treatment. Methods: We evaluated microRNA‐126 (miR‐126) levels in MDS patients' sample and in a NUP98‐HOXD13 (NHD13) murine MDS model along with their normal controls and defined its role in MDS HSPCs' maintenance by inhibiting miR‐126 expression in vitro and in vivo. Identification of miR‐126 effectors was conducted using biotinylated miR‐126 pulldown coupled with transcriptome analysis. We also tested the therapeutic activity of our anti‐miR‐126 oligodeoxynucleotide (miRisten) in human MDS xenografts and murine MDS models. Results: miR‐126 levels were higher in bone marrow mononuclear cells from MDS patients and NHD13 mice relative to their respective normal controls (P < 0.001). Genetic deletion of miR‐126 in NHD13 mice decreased quiescence and self‐renewal capacity of MDS HSPCs, and alleviated MDS symptoms of NHD13 mice. Ex vivo exposure to miRisten increased cell cycling, reduced colony‐forming capacity, and enhanced apoptosis in human MDS HSPCs, but spared normal human HSPCs. In vivo miRisten administration partially reversed pancytopenia in NHD13 mice and blocked the leukemic transformation (combination group vs DAC group, P < 0.0001). Mechanistically, we identified the non‐coding RNA PTTG3P as a novel miR‐126 target. Lower PTTG3P levels were associated with a shorter overall survival in MDS patients. Conclusions: MiR‐126 plays crucial roles in MDS HSPC maintenance. Therapeutic targeting of miR‐126 is a potentially novel approach in MDS. [ABSTRACT FROM AUTHOR]