Loss of Wdr5 attenuates MLL-rearranged leukemogenesis by suppressing Myc targets.

Lulu Liu, Xin Guo, Yao Wang,Guo Li,Yanyan Yu, Yang Song,Chenhui Zeng,Zhilou Ding, Yuanjun Qiu, Feifei Yan, Yi-Xiang Zhang,Caiqi Zhao,Yan Zhang,Yali Dou,Peter Atadja,En Li,He Wang

Biochimica et biophysica acta. Molecular basis of disease(2022)

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Abstract
WD repeat domain 5 (WDR5) is a prominent target for pharmacological inhibition in cancer through its scaffolding role with various oncogenic partners such as MLL and MYC. WDR5-related drug discovery efforts center on blocking these binding interfaces or degradation have been devoted to developing small-molecule inhibitors or degraders of WDR5 for cancer treatment. Nevertheless, the precise role of WDR5 in these cancer cells has not been well elucidated genetically. Here, by using an MLL-AF9 murine leukemia model, we found that genetically deletion of Wdr5 impairs cell growth and colony forming ability of MLL-AF9 leukemia cells in vitro or ex vivo and attenuates the leukemogenesis in vivo as well, which acts through direct regulation of ribosomal genes. Pharmacological inhibition of Wdr5 recapitulates genetic study results in the same model. In conclusion, our current study demonstrated the first genetic evidence for the indispensable role of Wdr5 in MLL-r leukemogenesis in vivo, which supports therapeutically targeting WDR5 in MLL-rearranged leukemia by strengthening its disease linkage genetically and deepening insights into its mechanism of action.
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