Thus, we provide first experimental in vivo evidence that CXCR4 hyperactivation supports and accelerates lymphoproliferation and CLL development in a susceptible genetic background, favoring development of a highly proliferative, nodally disseminating cancer with features of aggressive B-cell lymphoma or histiocytic sarcoma in a subset of Eμ-TCL1;CXCR4C1013G mice. Here, CXCR4 is linked to B-cell chronic lymphocytic leukemia.