Tet2 deficiency drives age-related heterogeneous progression of myeloid neoplasms through epigenetic-immune microenvironment imbalance
Tet2 dysfunction drives myeloid neoplasm initiation and progression, yet the mechanisms underlying disease heterogeneity, age-dependent progression and immune microenvironment perturbation remain poorly understood. This study aimed to establish a hematopoietic specific Tet2 conditional knockout mouse model to elucidate these core mechanisms and recapitulate clinical features of Tet2 mutated myeloid neoplasms. We generated Mx1-Cre-mediated haematopoietic-specific Tet2 conditional knockout mice on a C57BL/6JGpt background using CRISPR-Cas9 and Cre-LoxP technologies. Haematopoietic phenotypes, pathological features and immune microenvironment dynamics were systematically characterised in 5- and 12-month-old mice, with wild-type littermates as controls. Statistical analyses were applied for intergroup comparisons of phenotypic and immunological indices. Tet2 deficiency induced myeloid neoplasms with distinct age-dependent progression. Five-month-old mice exhibited mild hematological abnormalities without overt pathology, whereas 12-month-old mice developed typical myeloid neoplasm phenotypes including pancytopenia, splenomegaly, myelodysplasia, with heterogeneous subtypes spanning myelodysplastic syndrome, myeloproliferative neoplasm and acute myeloid leukemia. These mice were also accompanied by severe immune dysregulation. Mechanistically, Tet2-deficient bone marrow established an immunosuppressive niche characterised by M2-like macrophage polarisation and a skewed CCR4 ligand profile with elevated CCL22 and diminished CCL17, which selectively recruited Foxp3⁺ regulatory T cells. Concurrently, serum cytokine profiling revealed broad immune activation spanning Th1-type, Th2-type and Th17-type responses. Male mice exhibited significantly accelerated disease progression compared with females. Tet2 deficiency drives myeloid neoplasm progression through the synergy of epigenetic dysregulation, age-related hematopoietic stem cell damage and immune microenvironment imbalance. This model recapitulates core clinical features of elderly Tet2-mutated myeloid neoplasms and provides a preclinical platform for mechanistic investigation and the development of epigenetic and immune-targeted precision therapies.