A potential oversight of the model is the lack of in vitro BCR stimulation using αIgM antibodies, which has been shown to enhance in vitro CLL proliferation in combination with costimulatory signals, including a combination of CD40 and cytokine signaling.32 Although BCR signaling has been acknowledged as a key mechanism for CLL progression in vivo,33 we avoided the use of in vitro BCR stimulation to exclude differences between IGHV-mutated and IGHV-nonmutated CLL samples. Here, CD40 is linked to B-cell chronic lymphocytic leukemia.