2. Academic Validation
  3. Restoring MLL reactivates latent tumor suppression-mediated vulnerability to proteasome inhibitors

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

  • Oncogene. 2020 Sep;39(36):5888-5901. doi: 10.1038/s41388-020-01408-7.
Maolin Ge  # 1,  Dan Li  # 1,  Zhi Qiao  # 2,  Yan Sun  # 1,  Ting Kang 3,  Shouhai Zhu 1,  Shifen Wang 4,  Hua Xiao 2,  Chunjun Zhao 1,  Shuhong Shen 5,  Zhenshu Xu 6,  Han Liu 7
Affiliations

Affiliations

  • 1 Shanghai 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.
  • 2 State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China.
  • 3 Department of Oncology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, 200092, Shanghai, China.
  • 4 Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, 350001, Fuzhou, China.
  • 5 Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology & Oncology, Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China. [email protected].
  • 6 Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, 350001, Fuzhou, China. [email protected].
  • 7 Shanghai 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. [email protected].
  • # Contributed equally.
PMID: 32733069 DOI: 10.1038/s41388-020-01408-7
Abstract

MLL undergoes multiple distinct chromosomal translocations to yield aggressive leukemia with dismal outcomes. Besides their well-established role in leukemogenesis, MLL fusions also possess latent tumor-suppressive activity, which can be exploited as effective Cancer treatment strategies using pharmacological means such as Proteasome inhibitors (PIs). Here, using MLL-rearranged xenografts and MLL leukemic cells as models, we show that wild-type MLL is indispensable for the latent tumor-suppressive activity of MLL fusions. MLL dysfunction, shown as loss of the chromatin accumulation and subsequent degradation of MLL, compromises the latent tumor suppression of MLL-AF4 and is instrumental for the acquired PI resistance. Mechanistically, MLL dysfunction is caused by chronic PI treatment-induced epigenetic reprogramming through the H2Bub-ASH2L-MLL axis and can be specifically restored by histone deacetylase (HDAC) inhibitors, which induce histone acetylation and recruits MLL on chromatin to promote cell cycle gene expression. Our findings not only demonstrate the mechanism underlying the inevitable acquisition of PI resistance in MLL leukemic cells, but also illustrate that preventing the emergence of PI-resistant cells constitutes a novel rationale for combination therapy with PIs and HDAC inhibitors in MLL leukemias.

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