Targeting acute myeloid leukemia by drug-induced c-MYB degradation.
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Date
2018-04ICR Author
Author
Walf-Vorderwülbecke, V
Pearce, K
Brooks, T
Hubank, M
van den Heuvel-Eibrink, MM
Zwaan, CM
Adams, S
Edwards, D
Bartram, J
Samarasinghe, S
Ancliff, P
Khwaja, A
Goulden, N
Williams, G
de Boer, J
Williams, O
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Animals
Humans
Mice
Mebendazole
Proteasome Endopeptidase Complex
Proto-Oncogene Proteins c-myb
Oncogenes
Child
Infant
Female
Male
Leukemia, Myeloid, Acute
Proteolysis
Research team
Translational Genomics
Language
eng
Date accepted
2017-10-18
License start date
2018-04
Citation
Leukemia, 2018, 32 (4), pp. 882 - 889