A team of scientists led by Professor Cao at the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, announced on April 9 that they have generated the first base-resolution DNA methylome of human hematopoietic stem cells (HSCs) from patients with myelodysplastic syndromes (MDS). The findings were published in Volume 2, article number 19 of the journal Immunity & Inflammation.
The study provides new insights into how DNA methylation abnormalities contribute to MDS, a group of disorders caused by poorly formed or dysfunctional blood cells. By mapping these changes at single-base resolution, researchers hope to improve understanding and treatment options for high-risk MDS cases.
Using advanced sequencing techniques, the researchers compared HSCs from high-risk MDS patients with those from healthy donors. They found widespread hypermethylation within CpG island regions and hypomethylation within repetitive elements such as Alu sequences in MDS HSCs. Functional analysis showed that these differentially methylated regions are linked to genes involved in cancer-related pathways and key regulatory networks necessary for normal HSC function.
Key hematopoietic regulators identified include GFI1 and BMI1. The transcriptional regulatory region of GFI1 was found to be highly hypermethylated with reduced gene expression, while BMI1 showed hypomethylation and increased expression. The research also explored the role of TET2—a DNA demethylase frequently mutated in MDS—in maintaining normal stem cell function through regulation of specific target genes.
Experiments using mouse models demonstrated that loss of Tet2 leads to hypermethylation at the Gfi1 promoter and suppression of its expression, resulting in abnormal expansion of stem cell populations and features resembling MDS. This highlights how disruptions in the TET2-GFI1 axis may drive disease progression through effects on stem cell aging.
According to the authors, identifying this "epigenetic brake" offers "a new conceptual framework for understanding disease initiation at the HSC level." They added: "This dual pattern suggests that interventions targeting the DNA methylation status of the GFI1 gene or its downstream pathways hold promise for MDS therapy, particularly in TET2-mutant cases." The study supports developing combination strategies using DNA hypomethylating agents as potential treatments for high-risk forms of MDS.
