Forced homo-oligomerization of RARα leads to transformation of primary hematopoietic cells

SummaryAlmost 100% of APL patients carry chimeric transcripts encoding truncated RARα fused to homo-oligomerization domains from partner proteins. To gain further insights into the cellular transformation mechanisms mediated by RARα fusion proteins, thorough structure/function analyses have been performed and identified the POZ homo-oligomerization domain as the minimal transformation domain that is necessary and sufficient for PLZF-RARα-mediated in vitro transformation of primary hematopoietic cells. A transformation-incompetent PLZF-RARα mutant defective in homo-oligomerization but not corepressor interaction could be rescued by synthetic FKBP-oligomerization domains. Furthermore, an artificial FKBP-RARα construct not only mimicked various biochemical properties of bona fide RARα fusion proteins but also mediated an ATRA-dependent transformation. Taken together, these findings endorse an oligomerization-dependent mechanism for RARα-mediated transformation and suggest a potential avenue for molecular therapy.