CD4+ T cell-derived IL21 regulates stem cell fate in acute myeloid leukemia by activation of p38-MAPK signaling - Human AMK

Self-renewal programs in leukemia stem cells (LSCs) predict poor prognosis in acute myeloid leukemia (AML) patients. We identified CD4+ T cell-derived interleukin (IL) 21 as an important negative regulator of self-renewal of murine and human LSCs, but not hematopoietic stem cells. IL21/IL21R signaling favored asymmetric cell division and differentiation in LSCs through accumulation of reactive oxygen species (ROS) and activation of p38-MAPK signaling, resulting in reduced LSCs number and significantly prolonged survival in murine AML models. In human AML, serum IL21 at diagnosis was identified as an independent positive prognostic biomarker for outcome and correlated with better survival and higher complete remission rate in patients that underwent high-dose chemotherapy. IL21 inhibited primary AML LSCs function in vitro by activating ROS and p38-MAPK signaling and this effect was enhanced by cytarabine treatment. Consequently, promoting IL21/IL21R signaling on LSCs may be a novel approach to decrease stemness and increase differentiation in AML. Transcriptomic profiles of FACS-purified CD34+ AML LSCs of 4 patients cultured in presence and absence of recombinant human IL21 were assessed in biological replicates using Illumina Nova 6000.