Grant: Operating Grant - PA: Regional Partnership Program - Saskatchewan

Treatment of leukaemias often requires bone marrow transplantation and the subsequent anti-leukaemia immunotherapeutic response is crucial for cancer elimination. While cancer cells are frequently killed by the anti-leukaemia response, its efficiency is low in paediatric T cell leukaemia (T-ALL). This may be due to the ability of T-ALL cells to survive signals initiated by the Death Receptor (DR), Fas. Killing T-ALL cells by activating the other DRs, DR4 and DR5, is also inefficient, which hinders their utilization. This is unfortunate, as DR4 and DR5 kill specifically cancer cells, and represent attractive therapeutic targets. It is important to identify molecules, protecting T-ALL from DRs, as their suppression may enhance the anti-T-ALL response, and support involvement of DR4 and DR5 in T-ALL treatment. Eph receptors are cell-surface proteins that can transfer signals inside the cell. Our recently published work shows that two Eph receptors, EphB3 and EphB6, are expressed on T-ALL cells. Our work also shows that Eph receptors transmit signals inside leukaemic T cells and support their survival by blocking DR-induced molecular modifications. This strongly suggests Eph receptors may actively support T-ALL ability to escape the anti-leukaemia immune response and to survive activation of DR4 and DR5. We plan to identify the specific Eph receptor that supports survival of T-ALL cells and to investigate the mechanism of its action, as this protein is likely to represent a new efficient target for leukaemia therapy. We also plan to examine if this protein has the ability to rescue cancerous T cells from the anti-leukaemia immune response and from DR5 or DR4 activation in the animal model. Our work should reveal new mechanisms of T-ALL resistance and may trigger the development of novel T-ALL therapies, inhibiting specific Eph receptors to increase the efficiency of anti-leukaemia immunotherapeutic approaches and to involve DR5, and DR4 in T-ALL treatment.