Here we generated and characterized Eμ:TCL1-driven autochthonous models of high-risk CLL that are characterized by conditional B-cell-specific deletion of Atm or Trp53. Our novel models of Atm- or Trp53-deficient CLL might serve as preclinical platforms for the discovery and in vivo validation of molecular liabilities associated with these high-risk genetic aberrations in CLL. Here, TP53 is linked to B-cell chronic lymphocytic leukemia.