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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2637-2646
PLENARY PAPER
Interactions of STAT5b-RAR , a novel acute promyelocytic
leukemia fusion protein, with retinoic acid receptor and STAT3
signaling pathways
Shuo Dong and
David J. Tweardy
From the Section of Infectious Disease, Department of
Medicine, Baylor College of Medicine, Houston, TX, and the Shanghai
Institute of Hematology, Shanghai Rui-Jin Hospital, Shanghai, Peoples
Republic of China.
Signal transducer and activator of transcription (STAT) 5b-retinoic
acid receptor (RAR)  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-RAR resulted from an interstitial deletion on chromosome 17. To determine the molecular mechanisms of myeloid leukemogenesis and
maturation arrest in STAT5b-RAR+ APL and its
unresponsiveness to ATRA, we examined the effect of STAT5b-RAR on
the activity of myeloid transcription factors including RAR/retinoid
X receptor (RXR) , STAT3, and STAT5 as well as its molecular
interactions with the nuclear receptor corepressor, SMRT, and nuclear
receptor coactivator, TRAM-1. STAT5b-RAR bound to retinoic
acid response elements (RAREs) both as a homodimer and as a heterodimer
with RXR and inhibited wild-type RAR/RXR transactivation.
Although STAT5b-RAR 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-RAR and promyelocytic leukemia zinc finger
(PLZF)-RAR. SMRT was released from STAT5b-RAR/SMRT complexes by
ATRA at 10 6 M, whereas TRAM-1 became associated with
STAT5b-RAR at 107 M. The coiled-coil domain of STAT5b
was required for formation of STAT5b-RAR homodimers, for the
inhibition of RAR/RXR transcriptional activity, and for stability
of the STAT5b-RAR/SMRT complex. Thus, STAT5b-RAR contributes to
myeloid maturation arrest by binding to RARE as either a homodimer or
as a heterodimer with RXR resulting in the recruitment of SMRT and
inhibition of RAR/RXR transcriptional activity. In addition,
STAT5b-RAR and other APL fusion proteins may contribute to
leukemogenesis by interaction with the STAT3 oncogene pathway.
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