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

Leukemia
V Walf-VorderwülbeckeO Williams

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 ...Continue Reading

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Citations

May 30, 2019·Leukemia·Elena Armenteros-MonterrosoOwen Williams
Mar 31, 2019·The Oncologist·Julia ThieraufJochen K Lennerz
Feb 20, 2020·Cancers·Anna V WojcickiKathleen M Sakamoto
Nov 7, 2019·Journal of Alzheimer's Disease : JAD·Ariana GattGareth Williams
Jun 21, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mélanie LambertMarie-Hélène David-Cordonnier
Jun 30, 2018·International Journal of Hematology·Hisashi Takei, Susumu S Kobayashi
Aug 28, 2020·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Babita KaundalSubhasree Roy Choudhury
Dec 29, 2019·Scientific Reports·Lu CaoThomas J Gonda
Jul 14, 2021·Cancer Letters·Maria V YusenkoKarl-Heinz Klempnauer
Jul 27, 2021·Pharmacology Research & Perspectives·Edward J R FletcherSusan Duty
Sep 29, 2020·Virus Research·Richard KillickGareth Williams
Jan 8, 2022·Clinical & Experimental Metastasis·Kamila ŘíhováPetr Beneš

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