# Enhanced depletion of MLL-fusion proteins in acute leukemia: potential for improved therapeutic outcomes

## TL;DR

This study shows that combining two FDA-approved drugs can effectively target and eliminate MLL-fusion proteins in leukemia cells, improving treatment outcomes.

## Contribution

The study identifies niclosamide as a new drug for depleting MLL-fusion proteins and shows enhanced efficacy when combined with disulfiram.

## Key findings

- Niclosamide depletes MLL-fusion proteins in both AML and ALL leukemia cells.
- Combining disulfiram and niclosamide enhances MLL-fusion protein depletion and inhibits leukemogenic programs.
- The drug combination has minimal impact on normal hematopoietic progenitor cells.

## Abstract

Rearrangements of the MLL (KMT2A) locus are associated with aggressive leukaemia of both myeloid and lymphoid lineages, that present profound therapeutic challenges in pediatric and adult patient populations. MLL-fusion genes resulting from these rearrangements function as driving oncogenes and have been the focus of research aimed at understanding mechanisms underlying their leukemogenic activity and revealing novel therapeutic opportunities. Inspired by the paradigm of depleting the PML-RARA fusion protein in acute promyelocytic leukemia using all-trans retinoic acid and arsenic trioxide, we conducted a screen to identify FDA-approved drugs capable of depleting MLL-fusion protein expression in leukemia cells. Previously, we reported potent anti-leukemia effects of disulfiram (DSF), identified through this screen. In the present study, we demonstrate that another hit compound, niclosamide (NSM), is also able to deplete MLL-fusion proteins derived from a range of different MLL-fusion genes in both acute myeloid (AML) and acute lymphoid (ALL) leukemias. Loss of MLL-fusion protein appeared to result from inhibition of global protein translation by NSM. Importantly, combination of DSF with NSM enhanced MLL-fusion protein depletion. This led to more profound inhibition of downstream transcriptional leukemogenic programs regulated by MLL-fusion proteins and more effective killing of both MLL-rearranged AML and ALL cells. In contrast, DSF/NSM drug combination had little impact on normal hematopoietic progenitor cell differentiation. This study demonstrates that two FDA-approved drugs with excellent safety profiles can be combined to increase the efficacy of MLL-fusion protein depletion and elimination of MLL-rearranged leukaemia.

The online version contains supplementary material available at 10.1186/s40164-024-00556-w.