Published on April 01, 2026, in Volume 2, article number 19 of the journal Immunity & Inflammation , a collaborative team led by Prof. Cao at the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, along with Dr. Liangding Hu at the Fifth Medical Center of Chinese PLA General Hospital, and Professors Qian Zhang and Yanmei Han at the National Key Laboratory of Immunity and Inflammation, Naval Medical University, has generated the first base-resolution DNA methylome of human MDS HSCs. The study provides a comprehensive view of DNA methylation abnormalities at single-base resolution and uncovers a novel mechanism by which TET2 dysfunction contributes to MDS pathogenesis.
Using single-base resolution sequencing, the researchers systematically compared the DNA methylomes of HSCs from high-risk MDS patients with those from healthy donors. The analysis revealed distinct patterns of methylation dysregulation in MDS HSCs: widespread hypermethylation within CpG island regions, while hypomethylation within repetitive elements such as Alu sequences.
Functional analysis showed that differentially methylated regions associated with genes clustered in cancer-related pathways, as well as extrinsic signaling pathways and intrinsic transcriptional regulatory networks essential for HSC function. Integrating these findings, the team identified key hematopoietic regulators—including GFI1 and BMI1—as critical targets of aberrant DNA methylation in MDS HSCs. The transcriptional regulatory region of GFI1 exhibited pronounced hypermethylation accompanied by reduced expression, while BMI1 showed a pattern of DNA hypomethylation with corresponding upregulation.
TET2 is a DNA demethylase that catalyzes the stepwise oxidation of 5-methylcytosine, mediating the dynamic reversal of DNA methylation. Although TET2 is one of the most frequently mutated genes in MDS and other myeloid malignancies, how it maintains HSC homeostasis through regulation of DNA methylation at specific target genes in primitive HSCs has been a longstanding question.
Using MDS mouse models and Tet2 knockout mice, the researchers demonstrated that TET2 directly mediates DNA demethylation at the Gfi1 promoter. Loss of Tet2 resulted in hypermethylation of the Gfi1 promoter and transcriptional repression of Gfi1, leading to aberrant expansion of the hematopoietic stem and progenitor cell pool. Focusing on the MDS-like phenotype that develops in aged Tet2-deficient mice, the team further elucidated how the TET2-GFI1 axis suppresses malignant transformation of HSCs from the perspective of stem cell aging.
This study establishes the first base-resolution DNA methylome of human MDS HSCs, moving beyond the limitations of low-resolution approaches or candidate gene studies to provide a panoramic view of DNA methylation disruption in MDS. By integrating analysis of primary patient samples with genetically engineered mouse models, the research connects epigenetic enzyme mutations, DNA methylation abnormalities, and dysregulated transcription factor expression into a coherent pathogenic cascade. The identification of the TET2-GFI1 axis as an "epigenetic brake" that suppresses MDS "offers a new conceptual framework for understanding disease initiation at the HSC level," highlighted the authors.
The findings carry significant translational potential. While high-risk MDS HSCs exhibit global DNA hypermethylation, they also display region-specific DNA hypomethylation that plays a critical role in disease development. "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 authors pointed out. In conclusion, the study provides an epigenetic rationale and potential targets for developing combination strategies with DNA hypomethylating agents in high-risk MDS.
Reference
DOI: http://doi.org/10.1007/s44466-026-00034-4
About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.
Website: https://link.springer.com/journal/44466
About Professor Xuetao Cao from the Chinese Academy of Medical Sciences
Prof. Cao is an Academician of the Chinese Academy of Engineering, Director of the Center for Immunotherapy Research at the Chinese Academy of Medical Sciences, Chair of the Academic Committee of the State Key Laboratory of Immunity and Inflammation, and Chief Scientist for the National Major Science and Technology Project for Innovative Drug Development. His research focuses on basic mechanisms of innate immunity and inflammation, and translational studies in cancer immunotherapy.
About Professor Liangding Hu from the Chinese PLA General Hospital
Prof. Hu is a Professor and Chief Physician in the Department of Hematopoietic Stem Cell Transplantation at the Fifth Medical Center of Chinese PLA General Hospital. He has received the National Science and Technology Progress Award (First Class) and the Military Science and Technology Progress Award (First Class). His research focuses on clinical hematopoietic stem cell transplantation and transplant immunology.
