Here we show that decreasing Dnmt3b’s activities in vivo in Dnmt3b+/−, Dnmt3b+/CI, and Dnmt3bCI/CI mice results in development of various hematologic malignancies, mostly TCL and CLL, highlighting its tumor suppressor function in spontaneous lymphomagenesis. This evidence concerns the gene DNMT3B and B-cell chronic lymphocytic leukemia.