A large retrospective study has revealed that JAK2 gene fusions, long associated with highly aggressive forms of cutaneous T-cell lymphoma (CTCL), also appear in more indolent variants of the disease, raising new possibilities for earlier diagnosis and targeted treatment.
JAK2 Gene Fusion Identified Across Aggressive and Indolent CTCL
The research, conducted at a major US cancer referral centre and spanning 25 years of clinical data, between 2000 and 2025, examined 43 patients with CTCL who were found to carry fusions involving the Janus kinase 2 (JAK2) gene. These genetic alterations, typically linked to the rare and fast-moving primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (pcAETCL), were detected using advanced RNA sequencing and next-generation DNA sequencing technologies.
Surprisingly, the vast majority of patients with JAK2 fusions, 38 out of 43 (88%), had mycosis fungoides (MF), CD30-positive lymphoproliferative disorders (LPD), or clinical presentations overlapping these diagnoses. These forms of CTCL are usually considered slower-growing and less clinically aggressive. Only four cases of pcAETCL and one case of peripheral T-cell lymphoma not otherwise specified were identified.
The study found that JAK2 fusions involved 10 different gene partners, most commonly ATXN2L, CAPRIN1, and PCM1. Patients ranged in age from 16 to 65, with a median age of 45, and were predominantly male. Additional co-occurring genetic events were frequently observed, including mutations affecting epigenetic regulation and transcriptional control. However, neither the mutational burden, fusion type, nor fusion partner correlated clearly with whether a patient’s CTCL followed a mild or aggressive clinical course.
JAK2 Gene Fusion Shows Potential as Therapeutic Target
These findings challenge the traditional understanding that JAK2 fusions are confined to highly cytotoxic CTCL and suggest instead that they may represent an early molecular lesion capable of progressing toward more aggressive lymphoma over time, potentially influenced by aging or comorbid medical conditions.
Researchers say the results highlight an important diagnostic and therapeutic opportunity. The prominence of JAK2 fusions, across both aggressive and indolent CTCL, supports a broader role for JAK2-targeted therapies, particularly in early-stage MF and CD30-positive LPD, where such treatments have not been routinely considered.
As sequencing becomes more integrated into routine dermatologic oncology care, identifying JAK2 fusions may help clinicians detect higher-risk CTCL earlier and tailor treatments more precisely.
Reference
Geller S et al. JAK2 Fusions in Adult Patients with Mycosis Fungoides and CD30 Lymphoproliferative Disorders. 2025; doi: 10.1001/jamadermatol.2025.4688
