The 4 basal tg BCR systems employed by Iacovelli et al are shown.¹  Red circles: exo-antigen–independent inter- (or intra-) smIG autorecognition via HCDR3–FR2 (VRQ)/FR3 (YYC) engagements leading to autonomous BCR signals. Such inter-BCR self-engagement (intra-BCR less likely due to missing crosslinking) potentially occurs at the single-cell and intercellular level. Triangles: cognate antigens (dashed for low-affinity vs solid for high-affinity). Autonomous BCR interactions appear as prerequisites for leukemic outgrowth from the Eµ-TCL1 tg backbone, as there are no leukemias arising from the high-affinity IgHEL receptor, which lacked antigen-independent autonomous signaling in vitro. Additional influence of ligand affinity: low-affinity autoantigens like PtC or Sm drive leukemia-associated selection for their BCRs. However, a protumorigenic synergism was only observed for the PtC receptors, which in contrast to the low-responsive leukemic IgSm, elicited robust intracellular signals upon ligand engagement.