Project description:Azacitidine is used to treat patients with myelodysplastic syndrome, which alters epigenetic regulatory program that changes global gene expression by inhibiting DNA methylation. However, epigenomic factors affecting azacitidine response have not been studied in the context of chromatin. The efficacy of the hypomethylating agent differs by patient, leaving approximately 40% of patients fail to respond. Here, we demonstrate that chromatin accessibility features in patient-derived bone marrow cells can distinguish azacitidine responders from non-responders before treatment. Profiling chromatin accessibility from 23 high-risk myelodysplastic syndrome patients discovered that treatment response is strongly associated with distinct hematopoietic cell states. While non-responders showed enrichment of myeloid progenitor signatures, responders were characterized by elevated T cell populations. Notably, CD8+ T cells from non-responders exhibited selective loss of chromatin accessibility at TBX/EOMES binding sites, revealing a previously unrecognized link between T cell differentiation state and azacitidine response. These findings suggest the importance of immune cell differentiation and their activity in hypomethylating agent response for myelodysplastic syndromes, providing insights for patient stratification and treatment optimization based on the chromatin accessibility in high-risk myelodysplastic syndrome patients.
Project description:We used Illumina NGS for high-throughput profiling of the DNA methylome (ERRBS) for myelodysplastic syndrome (MDS) iPSC cell lines. We performed DNA methylation analysis of the low-risk MDS1.12 cells (iPSC cell line) treated with 5-AzaC- and show that profound hypomethylation changes can be detected following treatment with 5-AzaC and support the use of our stage-specific induced pluripotent stem cells system to study mechanisms of drug action.
Project description:This study aimed to find the functional circular RNA and further analyze its biological and clinical significance in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients.The circRNAs profiles were analyzed using the Arraystar human circRNA microarray with bone marrow samples from 5 MDS patients, 5 AML patients and 4 controls. Real-time quantitative polymerase chain reaction was carried on circZBTB46 in bone marrow samples from 124 MDS patients, 116 AML patients and 37 controls, and subsequently associated with clinicopathological characteristics and survival of MDS and AML patients.Furthermore, functional studies were conducted by silencing and rescuing/increasing circZBTB46 expression in SKM-1, THP-1 and K562 cell lines. Our results suggested the essential role of circZBTB46 in the progression of MDS and AML, and might be a poor indicator of hematological malignancies.
Project description:A role for reduced ribosomal protein gene dosage in both DBA and 5q- MDS suggests that other forms of MDS might also involve altered expression of ribosomal protein genes. We used microarrays to interrogate the expression of ribosomal proteins from purified hematopoietic stems cells from patients with low risk myelodysplastic syndrome and age-matched healthy controls. Hematopoietic stem cells were sorted from 8 patients with low risk myelodysplastic syndrome and 11 age-matched healthy controls, and total RNA was hybridized to Affymetrix microarrays.