Our models will not only permit prospective testing of the effects of stress or environmental factors on the Dnmt3a-mutant CH phenotype, but also whether effects on CH ultimately change the risk of progression to malignancy upon acquisition of a cooperating mutation in Npm1. Furthermore, orthogonal regulation of the Dnmt3a and Npm1 mutations will permit interrogation of the underlying biological mechanisms by which these mutations interact to cause malignancy, including hematopoietic cell-intrinsic interactions (ex. Here, NPM1 is linked to cyclic hematopoiesis.