Inhibition of MLLT1 limits growth of KMT2A::AFF1 leukaemias without killing healthy haematopoietic stem cells.

A major challenge in cancer therapeutics has been the identification of targets that are selectively toxic to cancer cells while displaying limited effects on healthy counterparts. Toxicities related to blood production from haematopoietic stem and progenitor cells (HSPCs) can be particularly problematic and can result in patient morbidity and mortality. MLLT1 has been identified as a key potential target in acute myeloid leukaemia. Here we evaluated the sensitivity of an MLLT1 inhibitor, SGC-iMLLT, on a panel of leukaemia cell lines and on healthy haematopoietic stem and progenitor cells (HSPCs). We found that SGC-iMLLT downregulated MLLT1 target genes and strongly inhibited KMT2A::AFF1-driven leukaemia growth in vitro and in vivo. By contrast, SGC-iMLLT did not alter in vitro colony forming potential of human HSPCs or affect long-term in vivo function of mouse HSPCs. These results suggest that SGC-iMLLT may have a promising therapeutic window in the treatment of KMT2A::AFF1-driven leukaemias, and that further clinical development is warranted. TeaserAbstract (1): A major challenge in cancer therapeutics has been the identification of targets that are selectively toxic to cancer cells while displaying limited effects on healthy counterparts. We evaluated a novel MLLT1 inhibitor, SGC-iMLLT, on a panel of leukaemia cell lines and on healthy haematopoietic stem and progenitor cells (HSPCs). SGC-iMLLT strongly inhibited MLL-AF4-driven leukaemia growth in vitro and in vivo, did not alter in vitro colony forming potential of human HSPCs or affect long-term in vivo function of mouse HSPCs. SGC-iMLLT may have a promising therapeutic window in the treatment of MLL-AF4-driven leukaemias.