chromatin immunoprecipitation analysis revealed binding of endogenous myc to the bcl2l11 locus in untransformed mouse embryo fibroblasts cultured in 10% serum . importantly , promoter occupancy was not saturated by endogenous myc , as activation of mycer resulted in increased binding . similar binding kinetics were observed at the bcl2l11 locus in non - transformed mcf10a human epithelial cells . strikingly , in these cells no myc binding , endogenous or inducible , was observed at other bh family genes , including bcl2 , bclx , bbc3 ( encoding puma ) , pmaip1 ( encoding noxa ) , bid , bad , bax , or bak . this contrasts with promoter occupancy of bh family genes in tumor cells derived from a genetically engineered mouse model of pancreatic cancer ; such cells express very high levels of myc and exhibit myc binding to all of the above promoters except for noxa and bak . although this difference might be explained by any number of factors , from tissue - specific chromatin configurations to differences between species , in light of recent reports studying promoter occupancy by different levels of myc , a very simple model emerges . we suggest that the bcl2l11 ( bim ) promoter contains high - affinity myc binding sites that are bound at lower ( i.e. , physiological or somewhat elevated ) levels of myc , whereas other bh family genes contain lower affinity binding sites and thus require higher levels of myc for binding ( fig . 1 ) . induction of bim by physiological levels of myc would not automatically drive apoptosis because a threshold level of bim induction is required to alone overcome anti - apoptotic buffering . such cells would nonetheless be  primed  to die in the presence of another pro - apoptotic signal or sub - optimal survival signaling . a striking example of this is the requirement for bim during tgf1-induced apoptosis in apc - deleted intestinal epithelium that expresses elevated levels of myc due to deregulated ctnnb1 activity . this model has 2 clear implications : ( 1 ) higher levels of myc elicit a stronger proapoptotic signal by engaging more bh family genes ; and ( 2 ) the requirement for bim can be overridden at very high levels of myc . tumor cells evolve continuously to cope with the challenges of relentless oncogenic signaling and survival in a hostile milieu . however , their adaptation is imperfect and rather like a series of stop - gap measures adopted under extreme duress . strategies to exploit this maladaption may lead to improved therapeutic response rates . augmenting intrinsic pro - death signals , for instance through the use of bh3 mimetics to overcome antiapoptotic buffering ,
in vivo analysis of the genetic determinants of myc - induced apoptosis reveals a specific requirement for the bcl2 family protein bim ( bcl2l11 ) . 
 surprisingly , apoptosis induced by myc in multiple solid tissues does not require p19arf ( cdkn2a ) , whereas puma ( bbc3 ) is required only in the context of sensitization by myc to death induced by dna damage .