Constitutive JAK3 Activation as a Mouse Model for Human Peripheral T-Cell Lymphoma.

Molecular pathogenesis of human peripheral T-cell malignancies remains poorly understood. We aimed to establish a model for these disorders by using the recently identified JAK3^A572V allele. This mutation, which lies in the pseudokinase (JH2) domain of JAK3, transforms Ba/F3 cells to factor-independent growth and causes a striking lymphoproliferative phenotype in a murine bone marrow transplantation assay. Further characterization of JAK3^A572V animals revealed that the aberrantly expanded cell population consisted of a mature effector/memory subtype of CD8⁺T-cells that infiltrated all major lymphoid and several non-lympoid organs and could be transplanted into secondary and tertiary recipients. These JAK3^A572V T-cells had increased proliferative capacities and displayed enhanced phosphorylation of common JAK3 targets, such as STAT5 and S6-kinase. Proliferation of primary T-cells transformed by JAK3^A572V was effectively inhibited with a small molecule JAK inhibitor that had no effect on the proliferative potential of control cells transduced with a wildtype JAK3 allele. Furthermore, the mutant cells showed increased production of cytotoxic cytokines, such as IFN-γ and TNF-α, compared to wildtype counterparts, which correlated with an increased cellular cytotoxicity towards allogeneic target cells. Of particular interest, JAK3^A572V animals presented with skin lesions and histopathologic analysis showed aberrant skin-homing T-cells tagging along the epidermal/dermal junctions. Mice receiving Rag1-deficient donor cells transduced with the JAK3^A572V allele also developed a lethal lymphoproliferative disease characterized by the expansion of immature CD3⁻TCRβ⁻CD4^+/−CD8⁺ cells, suggesting that the JAK3^A572V-dependent lymphoproliferation does not require proper TCR rearrangement. Altogether these results indicate that in this murine model, constitutive activation of JAK3 results in peripheral/cutaneous T-cell lymphoma (PTCL) that closely resembles the human disease. These findings suggest the possibility that the molecular basis of human PTCL could include aberrant JAK3 signaling and might provide a useful platform for deciphering the molecular and cellular mechanisms and requirements for peripheral lymphoid disease development and progression. Furthermore, it provides an opportunity to investigate the therapeutic potential of selective JAK3 inhibitors for this subset of lymphoid disorders, whose treatment remains a challenge.