The AhR agonist VAF347 augments retinoic acid‐induced differentiation in leukemia cells

In binary cell‐fate decisions, driving one lineage and suppressing the other are conjoined. We have previously reported that aryl hydrocarbon receptor (AhR) promotes retinoic acid (RA)‐induced granulocytic differentiation of lineage bipotent HL‐60 myeloblastic leukemia cells. VAF347, an AhR agonist, impairs the development of CD14+CD11b+ monocytes from granulo‐monocytic (GM) stage precursors. We thus hypothesized that VAF347 propels RA‐induced granulocytic differentiation and impairs D3‐induced monocytic differentiation of HL‐60 cells. Our results show that VAF347 enhanced RA‐induced cell cycle arrest, CD11b integrin expression and neutrophil respiratory burst. Granulocytic differentiation is known to be driven by MAPK signaling events regulated by Fgr and Lyn Src‐family kinases, the CD38 cell membrane receptor, the Vav1 GEF, the c‐Cbl adaptor, as well as AhR, all of which are embodied in a putative signalsome. We found that the VAF347 AhR ligand regulates the signalsome. VAF347 augments RA‐induced expression of AhR, Lyn, Vav1, and c‐Cbl as well as p47phox. Several interactions of partners in the signalsome appear to be enhanced: Fgr interaction with c‐Cbl, CD38, and with pS259c‐Raf and AhR interaction with c‐Cbl and Lyn. Thus, we report that, while VAF347 impedes monocytic differentiation induced by 1,25‐dihydroxyvitamin D3, VAF347 promotes RA‐induced differentiation. This effect seems to involve but not to be limited to Lyn, Vav1, c‐Cbl, AhR, and Fgr