Increase in serum IL-4 in response to venetoclax therapy in xenograft models of acute myeloid leukaemia

Abstract

Despite significant progress in basic and preclinical research into acute myeloid leukaemia (AML), the five-year survival rate for patients with AML remains poor, highlighting the urgent need for new combination therapies. Over the past decade, increased attention has been focused on identifying suitable immunotherapeutic strategies to combat AML, in particular targeting leukaemia cells and their precursors with cytokines. Targeted therapy is also an established approach for the treatment of AML. However, with the increasing number of treatment options, there are challenges in understanding how to select the most effective therapy and how to combine different drugs. Venetoclax is a targeted agent, a potent and highly selective inhibitor of B cell lymphoma protein-2 (BCL-2), one of the cell’s major anti-apoptotic proteins. Research into approaches to improve the treatment of AML remains challenging due to the limitations of experimental models. Despite improvements in ex vivo culture protocols, in vivo models remain the only way to study the inherently heterogeneous nature of AML and the influence of the microenvironment on leukaemia development. In our study, we show that in a xenograft mouse model of acute myeloid leukaemia in mice of the NSG-SGM3 line, there is an increase in serum IL-4 in response to venetoclax therapy. IL-4 has previously been shown to induce apoptosis in AML cells. These data provide new perspectives for the use of strategies based on the synergism of venetoclax and IL-4 in inducing apoptosis. The data also show an increase in serum human MCP-1 levels upon engraftment of OCI-AML-2 leukaemia cells in the serum of xenografted mice, which decreases after venetoclax therapy and may serve as a prognostic marker for the success of ongoing therapy. An obvious advantage of xenograft models in mice was the ability to separate the expression and secretion of murine cytokines and chemokines that determine the microenvironmental response from the cytokine profile of the human tumor cells themselves. Overall, our data suggest additional functional features of venetoclax action on tumor cells through the regulation of cytokine secretion and the prospect of using the immunodeficient mouse line NSG-SGM3 to test new approaches to the treatment of AML.