Using a combination of in vitro and in vivo studies and in silico analysis of patients' gene expression profiles, we show that in APL, PML-RARα functionally cooperates with HIF factors, particularly HIF-1α, and exploits the transcriptional repertoire of HIF-1α to promote not only LICs maintenance but also leukemia progression at multiple levels. The gene discussed is HIF1A; the disease is acute promyelocytic leukemia.