Upregulation of AXL and β-catenin in chronic lymphocytic leukemia cells cultured with bone marrow stroma cells is associated with enhanced drug resistance

Chronic lymphocytic leukemia (CLL) remains an incurable disease despite the development of numerous new compounds under investigation. Arsenic trioxide (ATO) has been shown to induce apoptosis in all types of CLL cells, suggesting its potential as an effective treatment. To further understand this, we examined how stromal cells, which are crucial components of the CLL microenvironment, affect CLL cell response to ATO. Our findings reveal that bone marrow stromal cells conferred resistance to 2 μM ATO in CLL cells, triggering the activation of Lyn, ERK, PI3K, PKC, NF-κB, and STAT3 pathways. Additionally, the expression of anti-apoptotic proteins such as Mcl-1, Bcl-xL, and Bfl-1 was upregulated during co-culture with stromal cells. Inhibition experiments demonstrated that PI3K and PKC played critical roles in stromal-induced ATO resistance. Furthermore, using specific inhibitors like idelalisib (PI3Kδ inhibitor) and sotrastaurin (PKCβ inhibitor) suppressed Akt phosphorylation, NF-κB/STAT3 activation, and Mcl-1 upregulation, sensitizing CLL cells to ATO. Mcl-1 was identified as a central factor in resistance, as its levels were directly correlated with CLL cell response to ATO, and blocking Mcl-1 with siRNAs or inhibitors overcame stromal protection. Thus, we have pinpointed the mechanism of resistance to ATO in CLL cells induced by bone marrow stroma, demonstrating that targeting this pathway with idelalisib or sotrastaurin can restore sensitivity to ATO. Combining ATO with these inhibitors could offer a TP-0903 promising therapeutic approach for CLL.