### Patient Information
This retrospective case series encompasses 43 adult patients diagnosed with cutaneous T-cell lymphoma (CTCL) found to harbor JAK2 gene fusions. The cohort consisted of 31 male (72.1%) and 12 female (27.9%) patients, with a median age of 45 years (range: 16-65 years). The patients were identified between 2000 and 2025 at a single US referral cancer center. The patients primarily presented with lesions consistent with mycosis fungoides (MF), CD30-positive lymphoproliferative disorders (LPD), or overlapping disease phenotypes, reflective of a spectrum from indolent to aggressive CTCL.
### Diagnosis
The diagnosis was established through molecular profiling employing a custom RNA sequencing panel and a targeted hybrid-capture-based next-generation DNA sequencing panel. These assays identified JAK2 gene fusions involving ten different partner genes, notably ATXN2L, CAPRIN1, and PCM1. Among the 43 patients, 38 (88.4%) presented with MF, CD30-positive LPD, or overlap syndromes, while 4 were classified as primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (pcAETCL), and 1 case was peripheral T-cell lymphoma not otherwise specified (PTCL NOS).
Secondary genetic alterations included mutations affecting epigenetic regulators and transcriptional machinery, but neither mutational burden nor the specific fusion partner correlated significantly with clinical stage or disease aggressiveness.
### Differential Diagnosis
– **Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (pcAETCL):** Distinguished by aggressive clinical behavior and cytotoxic phenotype; 4 cases in series confirmed by morphology and immunophenotyping.
– **Peripheral T-cell lymphoma, not otherwise specified (PTCL NOS):** One case differentiated by exclusion and molecular profile.
– **Other indolent CTCL variants:** Ruled out by molecular and histopathologic correlation.
### Treatment and Management
While detailed individual treatment regimens across the cohort were not extensively documented, the molecular findings suggest potential clinical implications for targeted therapy with JAK2 inhibitors. Patients with early-stage MF and CD30-positive LPDs, traditionally managed with skin-directed therapies or immunomodulation, might benefit from emerging JAK2-targeted treatments. The presence of JAK2 fusions indicates a rationale for integrating molecular testing into diagnostic workflows, potentially guiding personalized therapy decisions.
### Outcome and Prognosis
Data demonstrated the presence of JAK2 fusions in both indolent and aggressive CTCL forms, without a clear predictive value for initial clinical aggressiveness. The findings suggest some indolent cases bearing JAK2 fusions may represent precursor lesions with potential for progression, particularly with advancing age and associated comorbidities. Long-term follow-up is necessary to delineate prognosis and therapeutic responses in this subgroup.
### Discussion
This case series expands the understanding of JAK2 gene fusions beyond their established association with cytotoxic CTCL types like pcAETCL. The identification of these fusions in mycosis fungoides and CD30-positive LPDs suggests a broader role in CTCL pathobiology, including more indolent disease states. The presence of JAK2 gene fusions challenges the previous paradigm that they are exclusive to aggressive forms, promoting reconsideration of molecular screening in all CTCL presentations.
Notably, the recurrent fusion partners (ATXN2L, CAPRIN1, PCM1) implicate diverse oncogenic mechanisms and potential therapeutic targets. Secondary mutations affecting epigenetic and transcriptional regulators underscore the complex genetic landscape of CTCL and may influence disease progression.
Given that JAK2 inhibitors are available and approved in other hematologic malignancies, their trial in selective CTCL patients harboring JAK2 fusions is warranted. Molecular characterization could thus herald a precision medicine approach, improving outcomes especially in early-stage or overlapping CTCL cases where current treatments are limited.
### References
Geller S, Liao V, Lavin L, Tang H, Do M, Moy A, Virgen CA, Donnelly L, Pulitzer MP. JAK2 Fusions in Adult Patients With Mycosis Fungoides and CD30 Lymphoproliferative Disorders. JAMA Dermatol. 2025 Nov 26. doi:10.1001/jamadermatol.2025.4688. Epub ahead of print. PMID: 41296329.
