Loss of Tet2 Rewires the Aging Bone Marrow to Drive Blood Cancers, Mouse Study Shows

One of the most common genetic changes in aging human blood cells has now been reproduced in the laboratory with striking fidelity. In a study published in the Journal of Translational Medicine, researchers in Beijing report that deleting the Tet2 gene specifically within the hematopoietic system of mice is sufficient to drive the full spectrum of age-related myeloid neoplasms, from myelodysplastic syndrome to acute myeloid leukemia. The work, led by Yanxi Chen and Xiupeng Yang of Xiyuan Hospital at the China Academy of Chinese Medical Sciences, together with collaborators, offers one of the most complete experimental reconstructions to date of how a single epigenetic mutation interacts with aging and the immune microenvironment to produce clinically heterogeneous blood cancers.

Tet2 is an epigenetic regulator, an enzyme that chemically modifies DNA through the oxidation of 5-methylcytosine, thereby influencing which genes are accessible for transcription. Mutations that impair Tet2 function are extraordinarily frequent in the elderly: they define a large fraction of cases of clonal hematopoiesis of indeterminate potential, or CHIP, the age-related expansion of blood cell clones carrying somatic mutations without overt malignancy. CHIP is a well-established risk factor for myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML), yet the mechanisms by which Tet2 loss translates into such diverse disease outcomes, and why progression accelerates with age, have remained incompletely understood. The new study set out to close that gap with a purpose-built animal model.

Using CRISPR-Cas9 gene editing and the Cre-LoxP recombination system, the team generated Tet2 conditional knockout mice on a C57BL/6JGpt background, in which the gene could be deleted selectively in hematopoietic cells through Mx1-Cre-mediated recombination. This design ensured that the mutation was confined to the blood-forming compartment, mirroring the somatic, tissue-restricted nature of Tet2 mutations in patients. The researchers then systematically characterized hematopoietic phenotypes, pathological features and immune microenvironment dynamics at two ages, five and twelve months, comparing the knockout animals with wild-type littermates. The two time points were chosen to capture, respectively, an early adult stage and a stage corresponding to advanced age in the mouse lifespan.

The results revealed a clear age-dependent trajectory of disease. At five months, the Tet2-deficient mice showed only mild hematological abnormalities and no overt pathology, a picture reminiscent of early clonal hematopoiesis in humans. By twelve months, however, the animals had developed the classic features of myeloid neoplasms: pancytopenia, a depletion of circulating red cells, white cells and platelets; splenomegaly, an enlargement of the spleen reflecting extramedullary blood production; and myelodysplasia, the morphologically abnormal maturation of blood cell precursors in the bone marrow. Crucially, the diseased mice did not converge on a single diagnosis. Instead, they displayed heterogeneous subtypes spanning myelodysplastic syndrome, myeloproliferative neoplasm and acute myeloid leukemia, the very range of outcomes seen in elderly patients carrying Tet2 mutations.

This heterogeneity is one of the study’s most significant contributions. Clinical hematologists have long observed that Tet2-mutated patients progress along different paths, some developing ineffective blood cell production, others overproduction of myeloid cells, and still others frank leukemia, but animal models have struggled to capture this diversity. The finding that a uniform Tet2 deletion in a uniform genetic background produces divergent disease subtypes as mice age suggests that stochastic factors, secondary events or microenvironmental influences, rather than the mutation itself, determine which clinical entity emerges. The model therefore recapitulates not just the existence of Tet2-driven disease but its characteristic unpredictability.

Beneath the hematological phenotypes, the researchers uncovered a profound immune reconfiguration of the bone marrow. Tet2-deficient mice established an immunosuppressive niche characterized by the polarization of macrophages toward an M2-like state, a phenotype associated with tissue repair, immune suppression and tumor promotion. At the same time, the chemokine landscape of the marrow was skewed: levels of CCL22 were elevated while CCL17 was diminished. Both molecules are ligands for the CCR4 receptor, but this altered ligand profile had a selective consequence, preferentially recruiting Foxp3-positive regulatory T cells into the bone marrow. Regulatory T cells are the immune system’s brakes, and their accumulation within the tumor-bearing marrow creates an environment in which malignant clones are shielded from immune surveillance.

The immune perturbation was not confined to the marrow. Serum cytokine profiling revealed broad systemic immune activation spanning Th1-type, Th2-type and Th17-type responses, indicating that Tet2 deficiency provokes a body-wide inflammatory state even as it builds a locally immunosuppressive niche in the bone marrow. This combination, chronic peripheral inflammation alongside local immune evasion, mirrors concepts developed in tumor immunology more broadly and may help explain why patients with clonal hematopoiesis carry elevated risks not only of hematological malignancy but also of inflammatory and cardiovascular disease, although the present study focused on the myeloid neoplasm phenotype.

A further striking observation concerned sex differences. Male mice exhibited significantly accelerated disease progression compared with females, a result that resonates with epidemiological data showing higher rates of clonal hematopoiesis and myeloid neoplasms in elderly men than in elderly women. The biological basis of this disparity remains to be fully elucidated, but its reproduction in a controlled animal model, where environmental and hormonal variables can be standardized, provides a tractable experimental system for dissecting why male biology appears to amplify the consequences of Tet2 loss.

Taken together, the study supports a three-part mechanistic model: Tet2 deficiency drives myeloid neoplasm progression through the synergy of epigenetic dysregulation, age-related damage to hematopoietic stem cells, and imbalance of the immune microenvironment. Age emerges not as a passive backdrop but as an active collaborator, with the passage of time allowing the epigenetically compromised stem cell compartment and the progressively distorted immune niche to reinforce one another until overt malignancy appears. The CCL22-driven recruitment of regulatory T cells and the M2-like polarization of macrophages offer concrete, mechanistically defined targets at the interface between the mutant clone and its surroundings.

The translational implications are considerable. Because the model recapitulates the core clinical features of elderly Tet2-mutated myeloid neoplasms, including their heterogeneity, their age dependence and their immune microenvironment signatures, the authors position it as a preclinical platform for both mechanistic investigation and therapeutic development. Epigenetic therapies aimed at restoring or compensating for lost Tet2 function could be tested alongside immune-targeted approaches designed to reverse macrophage polarization, block CCR4-mediated recruitment of regulatory T cells, or rebalance the systemic cytokine storm. As the population ages and Tet2-mutated clonal hematopoiesis becomes an increasingly common incidental finding, models of this kind will be essential for deciding which carriers need intervention, and which of the emerging epigenetic and immunotherapeutic strategies can prevent a silent clone from becoming a lethal cancer.

Subject of Research: Tet2 deficiency and age-related progression of myeloid neoplasms through epigenetic and immune microenvironment dysregulation

Article Title: Tet2 deficiency drives age-related heterogeneous progression of myeloid neoplasms through epigenetic-immune microenvironment imbalance

Article References: Chen, Y., Yu, L., Yang, R., Chen, P., Zeng, W., Li, Z., Wang, Y., Xu, Y., & Yang, X. (2026). Tet2 deficiency drives age-related heterogeneous progression of myeloid neoplasms through epigenetic-immune microenvironment imbalance. Journal of Translational Medicine, 24(1), Article 1160. https://doi.org/10.1186/s12967-026-08835-2

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08835-2

Keywords: Tet2, clonal hematopoiesis, myeloid neoplasms, myelodysplastic syndrome, acute myeloid leukemia, epigenetics, bone marrow microenvironment, macrophage polarization, regulatory T cells, CCR4, mouse model, aging