Hidden T-Cell Clones Are Surprisingly Common in JAK2-Mutated Blood Cancers

A large retrospective study from China has uncovered a strikingly high burden of covert immune-cell clones in patients with JAK2-mutated myeloproliferative neoplasms, a family of chronic blood cancers that includes polycythemia vera and essential thrombocythemia. The research, published in Annals of Hematology by a team led by Weixia Zhuang, Lisha Lu, and Moufeng Wang, found that nearly one in five patients carrying the JAK2 driver mutation also harbored expanded populations of clonal T-large granular lymphocytes, a finding that far exceeds the rates observed in patients with other forms of the disease. The result suggests that the same mutated signaling machinery that drives uncontrolled blood-cell production may also be reshaping the immune system in ways that clinicians have largely overlooked.

Myeloproliferative neoplasms, or MPNs, arise when a hematopoietic stem cell acquires a mutation that lets it proliferate without normal restraint. The most common culprit is a mutation in JAK2, a gene encoding a tyrosine kinase that sits at the heart of the signaling pathway used by hormones such as erythropoietin and thrombopoietin. When JAK2 is activated by mutation, the cell receives a constant grow-and-survive signal, leading to overproduction of red cells, platelets, or both. A second, distinct category of MPN is driven by the BCR::ABL fusion gene, the hallmark of chronic myeloid leukemia, while a smaller fraction of cases are driven by mutations in CALR, the gene encoding calreticulin. Although these diseases are defined by myeloid-lineage expansion, hematologists have long suspected that lymphoid abnormalities, particularly expansions of T cells with a large granular appearance, occur more often in MPN patients than in the general population.

T-large granular lymphocytes, commonly abbreviated T-LGL, are cytotoxic T cells, the immune system’s specialized killers that normally patrol the body destroying virus-infected and malignant cells. When these cells expand clonally, meaning that a single T cell has proliferated into a large population of genetically identical descendants, the resulting condition can range from a benign laboratory curiosity to a frank lymphoproliferative disorder associated with neutropenia, anemia, and autoimmune disease. The diagnostic gold standard for detecting T-cell clonality has traditionally been T-cell receptor gene rearrangement studies, a molecular technique that is labor-intensive and not routinely applied to every patient. The new study instead leveraged a more accessible tool: flow cytometric assessment of TRBC1, a constant region of the T-cell receptor beta chain.

The logic behind TRBC1-based clonality testing is elegant. Mature T cells express either the TRBC1 or the TRBC2 version of the beta-chain constant region, and in a normal, polyclonal T-cell population the two versions are present in roughly equal proportions. If a single clone has expanded, however, virtually all of its cells will express only one version. The researchers therefore defined clonality as TRBC1 restriction, with either more than 85 percent or less than 15 percent of the relevant T cells staining positive for the marker. Combined with the characteristic LGL surface phenotype, defined as CD3 positivity together with expression of CD57 or CD56, this approach allowed the team to identify clonal expansions directly from routine flow cytometry data.

The study population comprised 354 consecutive MPN patients evaluated between January 2021 and April 2026: 182 with BCR::ABL-positive disease, 163 with JAK2 mutations, and 9 with CALR mutations. Clonal T-LGL expansions were detected in 34 patients overall, a detection rate of 9.6 percent across the entire cohort. But the distribution across mutation subgroups was anything but uniform. Among JAK2-mutated patients, 28 of 163, or 17.2 percent, carried clonal T-LGL populations. In the BCR::ABL-positive group, only 6 of 182 patients, or 3.3 percent, showed such expansions, and in the small CALR-mutated group none were detected at all. The difference between the JAK2 and BCR::ABL groups was highly statistically significant, with a chi-squared statistic of 18.45 and a P value below 0.001.

Why should JAK2-mutated patients be so much more prone to T-cell clonality than patients whose disease is driven by BCR::ABL? One plausible explanation lies in the biology of the founding mutation itself. JAK2 mutations are thought to arise early in hematopoiesis, potentially in a multipotent progenitor that retains the capacity to generate both myeloid and lymphoid lineages, so a JAK2-mutated clone may seed T cells as well as blood-forming cells. BCR::ABL, by contrast, is classically associated with a more committed progenitor. In addition, chronic JAK-STAT signaling has well-documented effects on the immune microenvironment, promoting inflammatory cytokine production that could chronically stimulate cytotoxic T cells and favor the outgrowth of particular clones. The authors are careful to note that their retrospective design cannot establish causation, but the mutation-specific pattern they observed is difficult to dismiss as coincidence.

The immunophenotypic portrait of the JAK2-associated clones proved remarkably diverse. Among the 28 JAK2-positive cases with clonal T-LGL, the overwhelming majority, 20 of 28 or 71.4 percent, were CD8-positive cytotoxic clones, while 4 cases, or 14.3 percent, were CD4-positive, 3 cases, or 10.7 percent, lacked both CD4 and CD8, and a single case, 3.6 percent, expressed the gamma-delta T-cell receptor rather than the conventional alpha-beta receptor. TRBC1 restriction ran in both directions: 17 of the 28 clones, or 60.7 percent, showed decreased TRBC1 expression below 15 percent, while 11, or 39.3 percent, showed increased expression above 85 percent. Aberrant loss or downregulation of pan-T-cell markers was frequent, with CD5 reduced or absent in 57.1 percent of cases and CD7 reduced or absent in 46.4 percent. CD57, a marker associated with terminal differentiation and replicative senescence, was expressed by 78.6 percent of the clones, whereas the natural-killer-associated marker CD56 appeared in 35.7 percent. The predominant immunophenotype was thus a CD8-positive, CD57-positive clone with aberrant CD5 or CD7 expression.

Beyond the T-cell findings, the study also probed whether these patients harbored other lymphoid clones. Among the 28 JAK2-positive patients with clonal T-LGL, two individuals, or 7.1 percent, had concurrent monoclonal B cells, indicating that in a small subset the lymphoid neoplastic process extends to more than one cell type. Notably, no monoclonal plasma-cell populations were identified in any patient. This layered co-occurrence of myeloid, T-cell, and B-cell clones in the same patients adds to a growing body of evidence that MPNs are not purely myeloid diseases but can exist within a broader field of clonal hematopoiesis, in which multiple genetically distinct cell populations compete and coexist in the bone marrow.

The clinical implications of the study are straightforward, and the authors do not shy away from a recommendation: routine TRBC1-based flow cytometric screening for T-cell clonality should be considered in JAK2-mutated MPN patients. Because the assay can be performed on the same flow cytometry panels already used to monitor these patients, the incremental cost and workload would be modest, while the diagnostic yield, at roughly one in six JAK2-positive patients, appears substantial. Identifying clonal T-LGL expansions matters because they can be associated with cytopenias, autoimmune phenomena, and, in some cases, progression toward overt T-cell lymphoproliferative disease. Knowing that a clone is present allows clinicians to establish a baseline, monitor its size over time, and interpret otherwise puzzling blood counts in the context of a second, independent clonal process.

Caveats remain. The study was retrospective, single-country, and included only nine CALR-mutated patients, a number far too small to draw conclusions about that subgroup, and the detection of clones does not by itself prove that they cause clinical harm in every carrier. Longitudinal follow-up will be needed to determine which clonal T-LGL populations remain stable, which regress, and which progress. Nevertheless, the work delivers a clear and actionable message: the immune landscape of JAK2-mutated myeloproliferative neoplasms is more crowded than standard workups reveal, and a simple flow cytometric marker, TRBC1, can bring that hidden clonal diversity into view. For a disease category long defined by its myeloid mutations, the T cells, it turns out, have a story of their own.

Subject of Research: Clonal T-large granular lymphocyte expansions in JAK2-mutated myeloproliferative neoplasms

Article Title: High prevalence and immunophenotypic diversity of clonal T‑large granular lymphocytes in JAK2‑mutated myeloproliferative neoplasms

Article References: Zhuang, W., Lu, L., Jiang, L., Chen, B., & Wang, M. (2026). High prevalence and immunophenotypic diversity of clonal T‑large granular lymphocytes in JAK2‑mutated myeloproliferative neoplasms. Annals of Hematology. https://doi.org/10.1007/s00277-026-07292-7

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07292-7

Keywords: myeloproliferative neoplasms, JAK2 mutation, T-large granular lymphocytes, TRBC1, flow cytometry, clonal hematopoiesis, CD8 T cells, BCR::ABL, CALR mutation, immunophenotyping, hematology, T-cell clonality