New treatments for high-risk paediatric acute lymphoblastic leukaemia

Abstract

Although long-term survival rates for childhood acute lymphoblastic leukaemia (ALL) are now approaching 90%, children with genetically specified subgroups remain at enhanced risk of treatment failure and reduced rates of survival. Among these subtypes, Philadelphia (Ph)-like ALL is correlated with the clinical features of higher risk, inadequate response to chemotherapy, high levels of minimal residual disease (MRD), early relapse and poor survival. The cytokine receptor like factor 2 (CRLF2) rearrangement and IKAROS family zinc finger 1 (IKZF1) deletion drive oncogenesis in a high proportion of paediatric Ph-like ALL patients; both CRLF2 and IKZF1 alterations drive stem cell renewal, cause abnormal bone marrow (BM) adhesion, and result in decreased chemosensitivity. The BM is the most frequent site of relapse in ALL. Therefore, this study focuses on how the BM microenvironment becomes supportive for the survival of Ph-like ALL cells following chemotherapy. Preclinical in vivo ALL patient-derived xenograft (PDX) models have shown in the present research that, when compared to other organs, induction chemotherapy is less effective in BM regions. Moreover, relapse-initiating MRD cells were higher in the BM regions of the Ph-like ALL PDX-bearing mice than was the case for the low-risk BCP-ALL PDXs, further suggesting substantial chemoresistance mechanisms of Ph-like ALL MRD cells in the BM. Accordingly, this study adopted a single-cell (sc)-RNA sequencing approach to identify how Ph-like ALL cells develop chemoresistance in the BM. Induction chemotherapy resulted in the suppression of TP53 and subsequent cell cycle alterations of Ph-like ALL cells, although this was not seen in low-risk BCP-ALL. In addition, both altered IKZF1 and CRLF2 rearrangement in Ph-like ALL confers glucocorticoid (GC) resistance. GCs form a critical component of chemotherapy regimens for paediatric ALL, with initial resistance to GC therapy being predictive of poor outcome. Interestingly, Ph-like ALL cell lines cocultured with BM stromal cells (BMSCs) exhibited increased resistance against GCs. However, IGF1R inhibitors, in combination with GCs, demonstrated remarkable in vitro efficacy when tested and compared to a Ph-like ALL cell line cocultured with BMSC. Overall, the data presented in this thesis provide novel insights into BM-induced chemoresistance in MRD cells, and could be used to facilitate the development of future therapeutic approaches in the treatment of Ph-like ALL.