We report that: 1) stromal cells induce CLL cell resistance to ATO via activation of the PI3Kδ-PKCβ/STAT3-NF-κB pathways; 2) Mcl-1 plays a central role in the mechanism of resistance to ATO; 3) blocking PI3Kδ and PKCβ with specific inhibitors overcomes the survival effect of stroma on CLL cells exposed to ATO. Here, PRKCB is linked to B-cell chronic lymphocytic leukemia.