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

Chronic myeloid leukemia arises when a reciprocal translocation between chromosomes 9 and 22, the so-called Philadelphia chromosome, fuses the BCR gene on chromosome 22 with the ABL1 gene on chromosome 9. The resulting BCR::ABL1 protein is a constitutively active tyrosine kinase that drives uncontrolled proliferation of myeloid cells. Imatinib mesylate, the first-generation tyrosine kinase inhibitor approved in the early 2000s, binds the ATP-binding pocket of this aberrant kinase and switches off its signaling, converting a once uniformly fatal disease into a manageable chronic condition for the vast majority of patients. Treatment success is typically monitored by measuring levels of BCR::ABL1 transcript through reverse transcriptase PCR, with a deep molecular response, known as a major molecular response, serving as a key benchmark of effective therapy.

The Indian case began, as many do, with a diagnosis of Philadelphia-positive chronic myeloid leukemia and initiation of imatinib therapy. But the diagnostic workup immediately revealed something unusual. Fluorescence in situ hybridization, or FISH, a technique that uses fluorescently labeled DNA probes to detect specific genetic rearrangements in cells, produced an atypical signal pattern that did not fit the standard picture of a simple BCR::ABL1 fusion. Conventional karyotyping, in which chromosomes are stained and examined under the microscope, showed additional cytogenetic abnormalities beyond the expected Philadelphia chromosome, raising the possibility of complex rearrangements and clonal evolution, features that in chronic myeloid leukemia are usually harbingers of disease progression and poor response to therapy.

To resolve the puzzle, the team deployed a systematic combination of the three cornerstone tools of leukemia genetics. Conventional cytogenetics mapped the chromosomal architecture of the leukemic clone. FISH with probes targeting the ABL1 and ETV6 loci revealed the presence of two distinct fusion events rather than one. Finally, reverse transcriptase PCR confirmed at the transcript level that the patient’s cells harbored both BCR::ABL1 and ETV6::ABL1 fusions concurrently. The ETV6 gene, located on chromosome 12, encodes a transcription factor that is itself a frequent partner in pediatric leukemias when fused to ABL1, but the coexistence of ETV6::ABL1 alongside BCR::ABL1 within a single case of chronic myeloid leukemia is exceptionally rare, and the authors emphasize that such dual ABL1-rearranged presentations are seldom documented in the literature.

The clinical implications of this double hit are where the case becomes genuinely paradoxical. On one hand, the patient failed to achieve a major molecular response throughout the entire course of imatinib therapy, a pattern consistent with resistance. The presence of two ABL1-fused transcripts provides a plausible mechanistic explanation: the ETV6::ABL1 fusion, like BCR::ABL1, encodes an activated tyrosine kinase, but the two fusion transcripts may respond differently to the drug, and the additional cytogenetic abnormalities suggest a genetically complex clone whose full burden is not eliminated by imatinib’s inhibition of a single kinase species. In this sense, the case illustrates how cytogenetic analysis can serve as the pivotal tool for uncovering the underlying cause of apparent imatinib resistance, a point the authors single out as the key highlight of their study.

On the other hand, and contrary to what the genetic complexity would predict, the patient demonstrated long-term survival on continued imatinib therapy. Complex rearrangements and additional chromosomal abnormalities in chronic myeloid leukemia are classically associated with accelerated progression, blast crisis, and poor outcomes, yet this patient’s disease followed an indolent trajectory despite persistent molecular evidence of active leukemia. The authors describe this combination, resistance at the molecular level coexisting with a benign clinical course, as a paradox, and it is precisely this tension that makes the case scientifically valuable. It suggests that the biological aggressiveness conferred by dual ABL1 fusions and clonal evolution may not map neatly onto the conventional prognostic framework, and that molecular response benchmarks, while indispensable for most patients, may not tell the whole story in genetically unusual leukemias.

Why might a patient with two active kinase fusions remain clinically stable on a drug designed to inhibit one of them? The report does not claim to fully answer this question, but several considerations emerge from the biology of these fusions. The ETV6::ABL1 fusion, though oncogenic, has been associated in some reported cases with variable clinical behavior, and the relative abundance, kinase domain sequence, and downstream signaling intensity of each fusion transcript may differ substantially between patients. Moreover, imatinib does inhibit ABL1 kinase activity regardless of which partner gene drives its expression, meaning both fusion proteins are pharmacologically targeted to some degree. The persistent failure to reach major molecular response may therefore reflect the sheer genetic burden of a complex clone rather than true pharmacological escape, while the indolent course may reflect that the residual disease retained a chronic-phase biology rather than acquiring the additional hits needed for blast transformation.

Beyond its immediate clinical narrative, the case carries a broader message about diagnostics in the era of targeted therapy. Modern molecular monitoring for chronic myeloid leukemia is built almost entirely around quantitative PCR assays designed to detect canonical BCR::ABL1 transcripts. A patient whose leukemia contains a second, noncanonical fusion could, in principle, have that driver overlooked entirely if workup stops at routine molecular testing. It was the atypical FISH signal pattern, an anomaly that would have been easy to dismiss as technical noise, that triggered the deeper cytogenetic investigation and ultimately revealed the dual fusion architecture. The authors argue that systematic documentation of such rare cases is essential for the efficient management of patients and for evolving the field’s understanding of dual oncogenic drivers in myeloid neoplasms, a sentiment that underscores the enduring value of conventional cytogenetics even in an age dominated by next-generation sequencing.

The report also speaks to a persistent theme in current chronic myeloid leukemia research. As the authors note, the field’s primary focus has been the discovery of new tyrosine kinase inhibitors and the elucidation of mechanisms underlying imatinib resistance, from kinase domain mutations to compound abnormalities. Cases like this one broaden that agenda by showing that resistance-like molecular profiles can arise from structural genomic complexity, including concurrent fusions, rather than from point mutations alone. For clinicians, the practical takeaway is that unexplained failure to achieve molecular milestones on imatinib warrants a full cytogenetic re-evaluation, including karyotyping and extended FISH panels, before assuming classic resistance mechanisms or escalating therapy. For researchers, the case adds to the small but growing catalog of leukemias with multiple ABL1 rearrangements, a population whose natural history remains poorly characterized precisely because it is so rare.

Published as an open-access case report and conducted with institutional ethics approval and patient consent, the study is a reminder that individual patients with unusual biology continue to teach medicine its most unexpected lessons. A leukemia that should have been aggressive behaved gently; a therapy that should have failed clinically succeeded in keeping the patient alive for the long term even as molecular benchmarks remained unmet. Untangling that paradox required nothing more exotic than careful, layered application of karyotyping, FISH, and PCR, the classic triad of leukemia genetics, applied with the persistence to chase an atypical signal pattern to its root. As tyrosine kinase inhibitors continue to evolve and molecular monitoring grows ever more sophisticated, this rare dual-fusion case stands as both a caution against over-reliance on single-marker testing and an argument for keeping the older, slower tools of cytogenetics firmly in the diagnostic toolkit.

Subject of Research: Concurrent ETV6::ABL1 and BCR::ABL1 fusion genes in a rare case of chronic myeloid leukemia with imatinib resistance

Article Title: Concurrent ETV6::ABL1 and BCR::ABL1 in a rare case of chronic myeloid leukemia: a paradox of imatinib resistance and indolent clinical course

Article References: Mohanty, P., Shetty, D., Amare, P., Patkar, N., Tembhare, P., Subramanian, P. G., Punatar, S., Gokarn, A., Jindal, N., & Khattry, N. (2026). Concurrent ETV6::ABL1 and BCR::ABL1 in a rare case of chronic myeloid leukemia: a paradox of imatinib resistance and indolent clinical course. Annals of Hematology. https://doi.org/10.1007/s00277-026-07234-3

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07234-3

Keywords: chronic myeloid leukemia, BCR::ABL1, ETV6::ABL1, imatinib resistance, tyrosine kinase inhibitor, cytogenetics, FISH, karyotyping, reverse transcriptase PCR, clonal evolution, myeloid neoplasms, ABL1 rearrangement