The Spleen is a Site of Residual Disease Following ABT-199 Treatment in Early T-cell Acute Lymphoblastic Leukaemia
thesisposted on 2021-12-14, 12:04 authored by Alessandra Di Grande
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.
First SupervisorDr. Tríona Ní Chonghaile
Second SupervisorProf. Jochen H. M. Prehn
CommentsSubmitted for the Award of Doctor of Philosophy to the Royal College of Surgeons in Ireland, 2020
Published CitationDi Grande A,. The Spleen is a Site of Residual Disease Following ABT-199 Treatment in Early T-cell Acute Lymphoblastic Leukaemia [PhD Thesis] Dublin: Royal College of Surgeons in Ireland; 2020
Degree NameDoctor of Philosophy (PhD)
Date of award2020-05-31
- Doctor of Philosophy (PhD)