A model for
adult T-cell leukemia/lymphoma
(ATL)
development. Loss of senescence response and/or inhibition or down-regulation of NF-κB activation (cells marked with green nuclei) drives clonal expansion of HTLV-1-infected cells (each marked with a “+” sign). Some of these cells, presumably precancerous, continue to evolve, propelled by the genomic instability caused by either Tax or the loss of RNF8, eventually giving rise to ATL. The frequent genetic alterations detected in ATLs, such as activating point mutations in phospholipase Cγ1 (PLCG1), vav guanine nucleotide exchange factor 1 (VAV1), and protein kinase Cβ (PKCB), activating point mutations and deletions in caspase recruitment domain-containing protein 11 (CARD11), CTLA4/CD152–CD28, and inducible T-cell COStimulator (ICOS)/CD278–CD28 fusions, homozygous deletion of cyclin-dependent kinase inhibitor 2A (CDKN2), and chemokine (C-C motif) receptor 4 (CCR4), CCR7, and G protein-coupled receptor 183 (GPR183) truncations, are incorporated into this model to stimulate discussions and suggest future experiments.