BCL11B, the Cerberus of human leukemia. The BCL11B locus resembles the 3-headed mythological creature Cerberus, because it is involved in various initiating oncogenic events for lineage-promiscuous AUL, T/M MPAL, AML M0/M1, ETP ALL, and T-ALL patients, although by virtue of different mechanisms. In patients with T-ALL, the BCL11B enhancer is highjacked by various oncogenes during early thymopoiesis. In a subtype of lineage-ambiguous patients whose disease expresses high levels of BCL11B or BCL11B-containing fusion transcripts and who are categorized as BCL11B-activated (BCL11B-a) patients, BCL11B acts as an oncogene because of its activation in early hematopoietic progenitor cells upon the chromosomal reposition of transcriptional regulatory sequences of specific loci as indicated. Alternatively, BCL11B can be driven from a 2.5-Kb region amplification located 700 Kb downstream of the BCL11B gene (denoted as BCL11B enhancer tandem amplification [BETA]). Most BCL11B-a patients are characterized by activating FLT3 mutations or have high JAK/STAT signaling activities that provide sensitivity to FLT3 or JAK/STAT inhibitors. The figure has been adapted from an etching by Antonio Tempesta (Florence, Italy, 1555-1630).