Drug repositioning for MLL-rearranged B-cell acute lymphoblastic leukaemia

Despite extensive research on therapeutic susceptibilities of different B-cell acute lymphoblastic leukaemia (ALL) subtypes, outcomes for MLL-rearranged ALL remain extremely poor. MLL rearrangements account for 70–80% of infant ALL cases and are associated with poor prognosis, less than 50% surviving current treatment regimens. Our group has developed a bioluminescence platform to screen for drugs which induce the degradation of MLL-fusion proteins. This platform was used to screen the Prestwick Chemical Library, which contains 1520 FDA-approved & EMA-approved drugs. We identified Disulfiram and Niclosamide as potential candidates which targeted MLL-fusion proteins for degradation. Interestingly, we found that neither drug was able to sensitise ALL cells to current conventional chemotherapies. Instead, they had an additive/synergistic inhibitory effect on RS4;11 (ZIP=4.5), SEMK2 (ZIP=3.7) and BEL-1 (ZIP=7.8) ALL cells. We further demonstrated that the combination of these 2 drugs downregulated MLL fusion target genes and induced apoptosis in ALL cells due to the degradation of MLL-fusion proteins. In this study, we provided a novel treatment regimen in MLL-rearranged ALL.

Publication History

Article published online:
17 May 2022