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Restoring MLL reactivates latent tumor suppression-mediated vulnerability to proteasome inhibitors

Maolin Ge1, Dan Li1, Zhi Qiao2

  • 1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.

Oncogene
|August 1, 2020
PubMed

Insights

Wild-type MLL is crucial for the tumor-suppressive activity of MLL fusions in leukemia. MLL dysfunction leads to proteasome inhibitor resistance, but HDAC inhibitors can restore MLL function.

Area of Science:

  • Hematology
  • Molecular Biology
  • Cancer Research

Background:

  • Chromosomal translocations involving the MLL gene are common in aggressive leukemias.
  • MLL fusions possess latent tumor-suppressive activity exploitable for cancer treatment.
  • Proteasome inhibitors (PIs) are investigated for MLL leukemia therapy.

Purpose of the Study:

  • To investigate the role of wild-type MLL in the tumor-suppressive activity of MLL fusions.
  • To elucidate the mechanism of acquired PI resistance in MLL leukemias.
  • To identify therapeutic strategies to overcome PI resistance.

Main Methods:

  • Utilized MLL-rearranged xenografts and MLL leukemic cell models.
  • Investigated MLL chromatin accumulation and degradation.
  • Analyzed the H2Bub-ASH2L-MLL axis and epigenetic reprogramming.
  • Assessed the effects of proteasome inhibitors (PIs) and histone deacetylase (HDAC) inhibitors.

Main Results:

  • Wild-type MLL is essential for the tumor-suppressive function of MLL fusions.
  • MLL dysfunction, involving loss of chromatin accumulation and degradation, compromises tumor suppression and drives PI resistance.
  • Chronic PI treatment induces epigenetic reprogramming via the H2Bub-ASH2L-MLL axis, leading to MLL dysfunction.
  • Histone deacetylase (HDAC) inhibitors restore MLL function by inducing histone acetylation and promoting MLL chromatin recruitment and cell cycle gene expression.

Conclusions:

  • MLL dysfunction is the mechanism underlying acquired PI resistance in MLL leukemias.
  • Targeting the H2Bub-ASH2L-MLL axis with HDAC inhibitors can restore MLL function and overcome PI resistance.
  • Combination therapy with PIs and HDAC inhibitors offers a novel strategy for MLL leukemias to prevent resistance.

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