Plenary paper Interactions of STAT5b-RARa, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways

Signal transducer and activator of transcription (STAT) 5b-retinoic acid receptor (RAR) a is the fifth fusion protein identified in acute promyelocytic leukemia (APL). Initially described in a patient with all-trans retinoic acid (ATRA)–unresponsive disease, STAT5b-RARa resulted from an interstitial deletion on chromosome 17. To determine the molecular mechanisms of myeloid leukemogenesis and maturation arrest in STAT5b-RARa1 APL and its unresponsiveness to ATRA, we examined the effect of STAT5b-RARa on the activity of myeloid transcription factors including RARa/retinoid X receptor (RXR) a, STAT3, and STAT5 as well as its molecular interactions with the nuclear receptor corepressor, SMRT, and nuclear receptor coactivator, TRAM-1. STAT5bRARa bound to retinoic acid response elements (RAREs) both as a homodimer and as a heterodimer with RXRa and inhibited wild-type RARa/RXRa transactivation. Although STAT5b-RARa had no effect on ligand-induced STAT5b activation, it enhanced interleukin 6–induced STAT3-dependent reporter activity, an effect shared by other APL fusion proteins including promyelocytic leukemia-RARa and promyelocytic leukemia zinc finger (PLZF)–RARa. SMRT was released from STAT5b-RARa/SMRT complexes by ATRA at 1026 M, whereas TRAM-1 became associated with STAT5b-RARa at 1027 M. The coiled-coil domain of STAT5b was required for formation of STAT5b-RARa homodimers, for the inhibition of RARa/ RXRa transcriptional activity, and for stability of the STAT5b-RARa/SMRT complex. Thus, STAT5b-RARa contributes to myeloid maturation arrest by binding to RARE as either a homodimer or as a heterodimer with RXRa resulting in the recruitment of SMRT and inhibition of RARa/RXRa transcriptional activity. In addition, STAT5b-RARa and other APL fusion proteins may contribute to leukemogenesis by interaction with the STAT3 oncogene pathway. (Blood. 2002;99: 2637-2646)