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Loss of MLL Induces Epigenetic Dysregulation of Rasgrf1 to Attenuate Kras-Driven Lung Tumorigenesis

Ling-Yu Zhu1, Jun-Bo Yuan1, Li Zhang1

  • 1Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen, Fujian, P.R. China.

Cancer Research
|September 13, 2022
PubMed

Insights

Mixed lineage leukemia (MLL) promotes Kras-driven lung tumorigenesis by regulating Rasgrf1 expression. Inhibiting MLL offers a targeted therapy for Kras-mutated lung cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Menin is a tumor suppressor crucial for the menin/mixed lineage leukemia (MLL) complex formation and chromatin recruitment.
  • MLL's role in menin-regulated lung tumorigenesis, particularly in Kras-mutated cancers, requires further investigation.

Purpose of the Study:

  • To elucidate the function of MLL in KrasG12D-induced lung tumorigenesis.
  • To explore the MLL-Rasgrf1 pathway as a therapeutic target in Kras-mutated lung cancer.

Main Methods:

  • Utilized a genetically engineered mouse model with KrasG12D mutation to study lung tumorigenesis.
  • Assessed the impact of MLL ablation on histone H3 lysine 4 trimethylation (H3K4me3) and Rasgrf1 gene expression.
  • Evaluated the efficacy of a small-molecule MLL inhibitor (MI-3) in Kras-mutated lung cancer models.

Main Results:

  • MLL ablation suppressed KrasG12D-induced lung tumorigenesis.
  • MLL deficiency led to decreased H3K4me3 and suppressed Rasgrf1 expression, crucial for Kras activation.
  • The MLL inhibitor MI-3 selectively inhibited Kras-mutated lung cancer cell growth in vitro and in vivo.

Conclusions:

  • MLL acts as a novel tumor promoter in mutant Kras-driven lung tumorigenesis.
  • The MLL-Rasgrf1 pathway is essential for Kras-driven lung cancer and represents a potential therapeutic target.

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