Because the S. cerevisiae genome contains only 2 copies of histone H3, HHT1 and HHT2, this model enables robust genetic screening to: (1) identify pathways and biological processes that are altered to support oncogenicity in mammals; and (2) apply this information to develop and design rational therapeutics for the treatment of oncohistone-driven cancers. Here, ACVRL1 is linked to cancer.