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

Direct Physical and Functional Interaction of the NuA4 Complex Components Yaf9p and Swc4p

Saccharomyces cerevisiae Yaf9p and the mammalian leukemia-associated protein ENL share a high degree of similarity. To investigate the biological function of Yaf9p, this protein was used to search for interacting proteins in a two-hybrid system. Here, we demonstrate that Yaf9p binds directly to Swc4p, the yeast homolog of the mammalian DNA-methyltransferase-associated protein 1. Yaf9p and Swc4p associate through C-terminal domains, and both proteins coprecipitate in vitro in pull-down experiments and in vivo by immunoprecipitation. In living cells, Swc4p is present in a megadalton protein complex that shows a fractionation behavior in gel filtration similar to that of Esa1p, the histone acetyltransferase of the NuA4 complex. Recruitment of Yaf9p to DNA leads to promoter-specific transcriptional activation that can be inhibited by dominant negative Swc4p lacking the Yaf9p binding domain. Interference with Swc4p function also increases sensitivity to the microtubule toxin benomyl, a trait that corresponds to the known phenotype of a yaf9(−) knockout strain. In summary, the results suggest that Yaf9p and Swc4p form a protein pair that has a role in chromatin modification with possible implications also for the function of their mammalian counterparts

Linking MLL Leukemia with Integrin Signaling

Identification of tractable signaling molecules essential for leukemogenesis facilitates the development of effective targeted therapies. In this issue of Cancer Cell, Miller and colleagues report that Integrin Beta 3, which is largely dispensable for normal hematopoiesis, plays an important role and is a potential therapeutic target in mixed lineage leukemia

A Knockout Combo:Eradicating AML Stem Cells with TKI plus SIRT1 Inhibition

SIRT1 inhibition facilitates elimination of CML stem cells by Imatinib, in part via p53 activation. In this issue of Cell Stem Cell, Li et al. (2014) demonstrate a similar role for SIRT1 inhibition in eradicating FLT3-ITD AML stem cells, potentially through a positive feedback loop with c-MYC, highlighting SIRT1 as a potential target in combination cancer therapy