Working model. (A) IL-15 receptor signaling in malignant cells (left) and normal CD4⁺ T cells (right). IL-15 cytokine binds its receptor complex α-β-γ to drive intracellular signaling, which includes reducing the level of miR-29b in cells. Decreased miR-29b releases negative regulation on BRD4 which then binds acetylated lysine residues on chromatin to direct gene expression. Upregulated genes include oncogenes and IL-15 receptor complex constituents, which drive cellular proliferation and resistance to apoptosis. Bortezomib inhibits the pathways that lead to decreased miR-29b expression, whereas JQ1 reduces BRD4 binding of chromatin, and both of these therapeutic strategies reduce oncogene and IL-15 receptor complex expression. In nonmalignant CD4⁺ T cells, miR-29b basal levels are higher, and BRD4 binding is relatively low. (B) IL-15 autocrine signaling loop. The regulatory pathway described facilitates formation of a self-sustaining autocrine loop that drives oncogene activation and cellular proliferation. This loop can be disrupted through use of bortezomib and JQ1.