Targeting acute myeloid leukemia by drug-induced c-MYB degradation.
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ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2018-04-01
Date Accepted
2017-10-18
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.
Citation
Leukemia, 2018, 32 (4), pp. 882 - 889
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
0887-6924
eISSN
1476-5551
Collections
Research Team
Translational Genomics