Targeting acute myeloid leukemia by drug-induced c-MYB degradation

Abstract

Despite advances in our understanding of the molecular basis for particular subtypes of acute myeloid leukemia (AML), effective therapy remains a challenge for many individuals suffering from this disease. A significant proportion of both pediatric and adult AML patients cannot be cured and since the upper limits of chemotherapy intensification have been reached, there is an urgent need for novel therapeutic approaches. The transcription factor c-MYB has been shown to play a central role in the development and progression of AML driven by several different oncogenes, including mixed lineage leukemia (MLL)-fusion genes. Here, we have used a c-MYB gene expression signature from MLL-rearranged AML to probe the Connectivity Map database and identified mebendazole as a c-MYB targeting drug. Mebendazole induces c-MYB degradation via the proteasome by interfering with the heat shock protein 70 (HSP70) chaperone system. Transient exposure to mebendazole is sufficient to inhibit colony formation by AML cells, but not normal cord blood-derived cells. Furthermore, mebendazole is effective at impairing AML progression in vivo in mouse xenotransplantation experiments. In the context of widespread human use of mebendazole, our data indicate that mebendazole-induced c-MYB degradation represents a safe and novel therapeutic approach for AML.

Clinically Integrated Molecular Diagnostics in Adenoid Cystic Carcinoma

“…Recently, xenografting and the first MYB‐NFIB‐positive cell line (UM‐HACC‐2A) have been established and represent interesting tools to explore novel therapeutic possibilities . Therapeutically, MYB‐targeted antisense oligodeoxynucleotides (G4460; INX‐3001; LR3001) have not been effective in clinical trials ; however, several lines of evidence suggest that MYB is a promising therapeutic target . Currently, the first clinical trial of a therapy that directly targets MYB, in combination with an anti‐PD‐1 immune checkpoint inhibitor, opened (MYPHISMO, NCT03287427), and the first patient with ACC received her first infusion of the MYB DNA vaccine in September 2018 .…”

Identification of drugs for leukaemia differentiation therapy by network pharmacology

“…We chose this drug due to its efficiency in inducing differentiation (in combination with ATRA) at relatively low doses. Recent studies showed that mebendazole reduces growth and viability of AML cell lines, and induces proteasomal degradation of the oncogenic TF c-MYB through inhibition of its association with the heat shock protein 70 (HSP70) chaperone system 25,48 . However, these studies did not investigate the effects of mebendazole on myeloid differentiation.…”

“…There is previous evidence that medendazole has anti-leukemic properties in AML 25 and indirectly interacts with tubulins according to the Therapeutic Target Database (TTD) 37 . Therefore we chose to experimentally test it, although it does not have expressed targets at 0h.…”

“…Mebendazole was also selected since it enhanced differentiation at relatively low doses. Furthermore, recent work indicated that mebendazole has anti-leukaemic activity in AML cells 25,48 , although no effects on differentiation were reported. Consistent with the flow cytometry results, neither dimaprit nor mebendazole alone induced differentiation at the morphological or functional levels.…”

“…CMAP has previously been used for drug repurposing 21,22,23 . By using input signatures specific to leukaemia cells or TFs as the input to CMAP, other studies have identified drugs which eliminate leukaemia cells, induce their differentiation or the loss of self-renewal 24,25,26,27 . Here we extend this approach at the network level, using Mogrify-identified TFs and their networks as the input signature for CMAP, to identify differentiation-inducing drugs.…”