The Spleen is a Site of Residual Disease Following ABT-199 Treatment in Early T-cell Acute Lymphoblastic Leukaemia

Abstract

T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive haematological malignancy arising in T cell progenitors. Early T-cell precursors leukaemia (ETPALL) is a particularly aggressive subgroup and associated with a high-risk of relapse. Over the last decade, intensified treatment strategies significantly improved the survival rate for T-ALL. However, 20% of paediatric and 50% of T-ALL adult patients are refractory to the treatment or relapsed (R/R). R/R patients have still limited therapeutic options and poor prognosis. Therefore, there is a need to develop more effective therapeutic strategies. Splenomegaly is often observed in T-ALL patients and was previously associated with poor prognosis However, the role of the splenic tumour microenvironment in response to specific treatments has not been extensively studied. ETP-ALL is dependent on the anti-apoptotic protein BCL-2 for survival and therefore ABT-199 (selective BCL-2 BH3 mimetics) could be a potential therapeutic option.In this study, cell line-based xenograft and PDX models of ETP-ALL were used to identify sites of minimal residual disease following ABT-199 treatment in vivo. We revealed the spleen is a site of residual disease for the more immature ETP-ALL subtype following ABT-199 treatment. Residual blasts isolated from the spleen had reduced dependence on BCL-2 along with reduced BCL-2 expression. The generation of ABT-199 resistance in LOUCY cells in vitro phenocopies the reduced BCL-2 dependence with a switching from BCL-2 to BCL-XL dependence. Human splenic fibroblasts (HS-F) co-cultured with the LOUCY cells induced the same alterations with a reduction in BCL-2 dependency and a reduced expression of BCL-2. Using an in vitro screening approach, we discovered an increased expression of IL-6 in the HS-F co-culture along with upregulation of the correspondent IL-6 receptor (IL-6 Ra). Blocking IL-6 Ra is able to reverse the change in BCL-2 dependence in vitro, suggesting that IL-6 signalling may be responsible, in part, for the phenotype observed upon co-culture with the HS-F. Of great interest, IL-6 Ra is highly expressed in immature T-ALL patient samples. Lastly, using a primary ETPALL patient-derived xenograft model on relapse, we further observed evidence of residual blasts in the spleen following ABT-199 treatment along with higher IL-6 levels. Collectively, this data reveals an important and previously undescribed function for the spleen, as a potential site of disease relapse following ABT-199 treatment and provides a rational to combine BCL-2 inhibitors with agents that can block IL-6 receptor signalling in the future.</div