Translocations of retinoic acid receptor-α (), typically , are a genetic hallmark of acute promyelocytic leukemia (APL). However, because a small fraction of APL lack translocations of , we focused here on APL cases without translocation to elucidate the molecular etiology of -negative APL. We performed whole-genome sequencing, PCR, and FISH for five APL cases without translocations. Four of five -negative APL cases had translocations involving retinoic acid receptor-β () translocations, and was identified as an in-frame fusion in three cases; one case had an rearrangement detected by FISH, although the partner gene could not be identified. When transduced in cell lines, homodimerized and diminished transcriptional activity for the retinoic acid receptor pathway in a dominant-negative manner. enhanced the replating capacity of mouse bone marrow cells and inhibited myeloid maturation of human cord blood cells as did. However, the response of APL with translocation to retinoids was attenuated compared with that of , an observation in line with the clinical resistance of -positive APL to ATRA. Our results demonstrate that the majority of -negative APL have translocations, thereby forming a novel, distinct subgroup of APL. as an oncogenic protein exerts effects similar to those of , underpinning the importance of retinoic acid pathway alterations in the pathogenesis of APL. These findings report a novel and distinct genetic subtype of acute promyelocytic leukemia (APL) by illustrating that the majority of APL without RARA translocations harbor RARB translocations. .