The BAALC/miR-3151 locus on chromosome 8q22 contains both the BAALC gene (for brain and acute leukemia, cytoplasmic) and miR-3151, which is located in intron 1 of BAALC. Older acute myeloid leukemia (AML) patients with high expression of both miR-3151 and the BAALC mRNA transcript have a low survival prognosis, and miR-3151 and BAALC expression is associated with poor survival independently of each other. We found that miR-3151 functioned as the oncogenic driver of the BAALC/miR-3151 locus. Increased production of miR-3151 reduced the apoptosis and chemosensitivity of AML cell lines and increased leukemogenesis in mice. Disruption of the TP53-mediated apoptosis pathway occurred in leukemia cells overexpressing miR-3151 and the miR-3151 bound to the 3' untranslated region of TP53. In contrast, BAALC alone had only limited oncogenic activity. We found that miR-3151 contains its own regulatory element, thus partly uncoupling miR-3151 expression from that of the BAALC transcript. Both genes were bound and stimulated by a complex of the transcription factors SP1 and nuclear factor κB (SP1/NF-κB). Disruption of SP1/NF-κB binding reduced both miR-3151 and BAALC expression. However, expression of only BAALC, but not miR-3151, was stimulated by the transcription factor RUNX1, suggesting a mechanism for the partly discordant expression of miR-3151 and BAALC observed in AML patients. Similar to the AML cells, in melanoma cell lines, overexpression of miR-3151 reduced the abundance of TP53, and knockdown of miR-3151 increased caspase activity, whereas miR-3151 overexpression reduced caspase activity. Thus, this oncogenic miR-3151 may also have a role in solid tumors.