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

Lulu Liu1, Xin Guo2, Yao Wang2

  • 1Novartis Institutes for BioMedical Research, 181 Massachusetts Ave., Cambridge, MA 02139, USA; Novartis Institutes for BioMedical Research, 4218 Jinke Road, Shanghai 201203, China.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|November 19, 2022
PubMed

Insights

Genetic deletion of WD repeat domain 5 (WDR5) impairs leukemia cell growth and formation, highlighting its crucial role in MLL-rearranged leukemia development. This study provides key genetic evidence supporting WDR5 as a therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • WD repeat domain 5 (WDR5) is a key scaffolding protein implicated in cancer, particularly through its interactions with oncogenic partners like MLL and MYC.
  • Current therapeutic strategies focus on small-molecule inhibitors or degraders targeting WDR5's binding interfaces.
  • The precise genetic role of WDR5 in cancer cells remains incompletely understood.

Purpose of the Study:

  • To genetically elucidate the role of WDR5 in MLL-rearranged leukemia.
  • To investigate the mechanism by which WDR5 influences leukemogenesis.
  • To provide genetic validation for WDR5 as a therapeutic target in MLL-rearranged leukemia.

Main Methods:

  • Utilized an MLL-AF9 murine leukemia model for genetic deletion studies.
  • Assessed cell growth and colony-forming ability in vitro and ex vivo.
  • Evaluated leukemogenesis in vivo.
  • Administered pharmacological WDR5 inhibitors to compare with genetic findings.

Main Results:

  • Genetic deletion of Wdr5 significantly impaired MLL-AF9 leukemia cell growth and colony formation.
  • Wdr5 deletion attenuated leukemogenesis in vivo.
  • Pharmacological inhibition of Wdr5 mirrored the effects observed in genetic studies.
  • WDR5 was found to directly regulate ribosomal genes, impacting leukemia progression.

Conclusions:

  • This study provides the first genetic evidence for the essential role of WDR5 in MLL-rearranged (MLL-r) leukemogenesis.
  • The findings genetically strengthen the link between WDR5 and MLL-r leukemia.
  • Targeting WDR5 therapeutically is supported by this genetic evidence, offering new insights into its mechanism of action.
Keywords:
MLL-rearranged leukemiaMyc targetsRibosome genesWdr5

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