The spleen as a site of relapse for early T-cell progenitor leukaemia
Dr T Chonghaile
Prof J Prehn
Monday, December 02, 2019
Competition Funded PhD Project (Students Worldwide)
Early T-cell progenitor ALL (ETP-ALL) originates from a block at early stages of T-cell development, has a poor prognosis with risk for relapse. We previously identified that ETPALL is dependent on the anti-apoptotic protein BCL-2 for survival and is sensitive to the BH3 mimetic, ABT199 (venetoclax). Patients diagnosed with ETP-ALL present with blast cells in the blood, bone marrow; and often in the spleen and in the lymph nodes. The spleen is an important site for extramedullary haematopoiesis and splenomegaly in patients is often associated with a poor prognosis. Of note, there is very limited research in leukaemia on the splenic microenvironment. In addition, it is not known how ETPALL interaction with distinct microenvironments affects the chemosensitivity and anti-apoptotic dependence.
We have evidence that the spleen may be a potential site of relapse for ETP-ALL treated with ABT-199. Using cytokine arrays, CRISPR-cas9 technology and BH3 profiling we aim to discern the mechanism. Next, we aim to measure the sites of relapse of ETP-ALL xenograft in vivo to ABT-199 and whether the protective niche in the spleen is driven by cytokine signalling. A recent case report has described the first ETP-ALL patients that have been treated with ABT-199. Our research into sites of relapse following venetoclax treatment could lead to improved therapeutic responses, in this group of patients with high-risk disease.