2014 - DYNAMIN-DEPENDENT ENDOCYTOSIS IS REQUIRED FOR MULTIPLE NICHE SIGNALS THAT ARE CRUCIAL FOR LEUKEMIA STEM CELL ACTIVITY AND CHEMORESISTANCE

The hierarchical model posits that acute leukemias arise from leukemia stem cells (LSCs), which display stem cell-like properties like long-term self-renewal and differentiation to generate the heterogeneity observed in the tumor at diagnosis. Elimination of LSCs and their ancestral clones, pre-leukemic stem cells (pre-LSCs), is critical for long-term cure as they are the source of relapse. How these cells survive high-dose therapy remains poorly defined, but may include quiescence and pro-survival signals provided by the microenvironment. Strategies to interfere with specific signals from the niche have shown promising results, but may be subject to compensatory mechanisms due to the inherent plasticity of LSCs. The transactivation of signalling pathways downstream of growth factors from the niche is dependent on receptor-mediated endocytosis, a generic process dependent on Dynamins. Given the important role of the microenvironment for relapse-inducing cells, we postulated that inhibition of Dynamin might impair their properties and sensitize them to chemotherapy. Here, we show that the Dynamin small molecule inhibitor Dynole 34-2 blocks multiple signalling pathways in pre-LSCs and LSCs by preventing endocytosis. Using the Lmo2-transgenic mouse model of T-cell acute lymphoblastic leukemia (T-ALL), we found that Dynole 34-2 impairs self-renewal of pre-LSCs and sensitizes relapse-inducing cells to chemotherapy. We also found that Dynole 34-2 delayed leukemia onset in mice treated with high-dose therapy. Treatment of different patient-derived xenografts revealed that that inhibition of Dynamin activity with Dynole 34-2 represents an effective therapeutic strategy for different subtypes of human T-ALL. In summary, our finding that Dynamin activity is essential for LSC activity and chemoresistance in acute leukemia paves the way for novel therapeutic strategies.