Rltpr Q575e: A Novel Recurrent Gain-Of-Function Mutation In Patients With Adult T-Cell Leukemia/Lymphoma

Objectives: Adult T-cell leukemia/lymphoma (ATL) is an intractable T-cell malignancy caused by long-term infection with human T-cell leukemia virus type-1 (HTLV-1). While ATL pathogenesis has been associated with HTLV-1-derived oncogenic proteins, including Tax and HBZ, the contribution of genomic aberrations remains poorly defined.Methods: To elucidate the genomic basis of ATL, whole exome sequencing was performed on cells from 47 patients with aggressive ATL.Results: We discovered the novel mutation RLTPR Q575E in four patients (8.5%) with a median variant allele frequency of 0.52 (range 0.11-0.68). Despite being reported in cutaneous T-cell lymphoma, three ATL patients carrying RLTPR Q575E lacked skin involvement. Patients carrying RLTPR Q575E also harbored CARD11 (75%), PLCG1 (25%), PRKCB (25%), or IKBKB (25%) mutations related to TCR/NF-kappa B signaling. Jurkat cells transfected with RLTPR Q575E cDNA displayed increased NF-kappa B activity and significantly increased IL-2 mRNA levels under stimulation. RLTPR Q575E increased the interaction between RLTPR and CARD11, while RLTPR directly interacted with Tax.Conclusions: We identified, and functionally validated, a novel gain-of-function mutation in patients with aggressive ATL. During TCR activation by Tax or gain-of-function mutations, RLTPR Q575E selectively upregulates NF-kappa B signaling and may exert oncogenic effects on ATL pathogenesis.