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Leukemia. 2018 Apr;32(4):882-889. doi: 10.1038/leu.2017.317. Epub 2017 Nov 1.

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

Author information

1
Cancer Section, Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, UK.
2
UCL Genomics, UCL Great Ormond Street Institute of Child Health, London, UK.
3
Department of Pediatric Oncology/Hematology, Erasmus-MC Sophia Children's Hospital, Rotterdam, The Netherlands.
4
Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
5
SIHMDS-Haematology, Great Ormond Street Hospital for Children, London, UK.
6
Department of Paediatric Haematology, Great Ormond Street Hospital for Children, London, UK.
7
Department of Haematology, UCL Cancer Institute, London, UK.
8
Wolfson Centre for Age-Related Diseases, King's College London, London, UK.

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.

PMID:
29089643
DOI:
10.1038/leu.2017.317

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