BAFF elevations and alloantigen stimulation promote a hyperresponsive GL7⁺ B-cell subset in cGVHD by stabilizing SYK after BCR signaling and inducing NOTCH2 expression. BAFF produced by follicular reticular cells (not shown) and T_FH cells has multiple effects on GL7⁺ B cells, which result in hyperresponsiveness to BCR signaling. Targets for therapeutic intervention are shown and may perhaps be synergistically tested for clinical efficacy. Ag, antigen; AKT, AKT kinase; Allo IgG, allogeneic immunoglobulin G; BAFF R, BAFF receptor; BCL6, B-cell lymphoma 6 protein; BCR, B-cell receptor; BIM, Bcl-2 interacting mediator of cell death; BLNK, B-cell linker protein; BTK, Bruton’s tyrosine kinase; ERK, extracellular signal-regulated kinase; IFN-γ, interferon-γ; IL-17, interleukin-17; IL-21, interleukin-21; IL-21R, interleukin-21 receptor; Jakinibs, JAK inhibitors; KD025, Kadmon therapeutic agent 025 (orally available ROCK2 inhibitor); mAb, monoclonal antibody; ROCK2, Rho-associated kinase 2; SYK, spleen tyrosine kinase.