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.
To elucidate the genomic basis of ATL, whole exome sequencing was performed on cells from 47 patients with aggressive ATL.
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-κB signaling. Jurkat cells transfected with RLTPR Q575E cDNA displayed increased NF-κB 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.
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-κB signaling and may exert oncogenic effects on ATL pathogenesis.

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