IL-21/IL-21R signaling renders acute myeloid leukemia stem cells more susceptible to cytarabine treatment and CAR T cell therapy

Self-renewal programs in leukemia stem cells (LSCs) predict poor prognosis in patients with acute myeloid leukemia (AML). We identify CD4 + T cell-derived interleukin (IL)-21 as an important negative regulator of self-renewal of LSCs. IL-21/IL-21R signaling favors asymmetric cell division and differentiation in LSCs through the activation of p38-MAPK signaling, resulting in reduced LSC numbers and significantly prolonged survival in murine AML models. In human AML, serum IL-21 at diagnosis is identified as an independent positive prognostic biomarker for outcome and correlates with improved survival and higher complete remission rates in patients that underwent high-dose chemotherapy. IL-21 treatment inhibits primary LSC function and enhances the effect of cytarabine and CD70 CAR T cell treatment on LSCs in vitro . Low-dose IL-21 treatment prolongs the survival of AML mice in syngeneic and xenograft experiments. Therefore, promoting IL-21/IL-21R signaling on LSCs may be an approach to reduce stemness and increase differentiation in AML. • CD4 + T cell-derived IL-21 reduces stemness and promotes the differentiation of AML LSCs • IL-21 reduces LSC function by activating ROS and p38-MAPK signaling • Low-dose IL-21 treatment prolongs the survival of MLL-AF9 and PDX AML mice • IL-21 treatment synergized with ARA-C and CAR T cell treatment Rubino et al. show that CD4 + T cell-derived IL-21 promotes LSC differentiation by activating MAPK signaling and that IL-21 treatment synergistically reduces LSCs in combination with chemotherapy and CAR T cell treatment. These results provide a rationale for the use of IL-21 in the treatment of patients with AML.