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KMT2D Deficiency Promotes Myeloid Leukemias which Is Vulnerable to Ribosome Biogenesis Inhibition

Jing Xu1, Ailing Zhong1, Shan Zhang1

  • 1Department of Hematology, Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|May 4, 2023
PubMed

Insights

Loss of the KMT2D gene accelerates acute myeloid leukemia (AML) in mice by enhancing ribosome production. Inhibiting ribosome biogenesis shows promise for treating KMT2D-deficient AML.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • KMT2C and KMT2D are frequently mutated epigenetic regulators in cancer.
  • KMT2C acts as a tumor suppressor in acute myeloid leukemia (AML).
  • The role of KMT2D in AML is currently unclear, though its loss is linked to other cancers.

Purpose of the Study:

  • To investigate the role of KMT2D in acute myeloid leukemia (AML).
  • To explore the molecular mechanisms underlying KMT2D's function in AML.
  • To identify potential therapeutic strategies for KMT2D-deficient AML.

Main Methods:

  • Gene knockdown using shRNA and gene editing with CRISPR/Cas9 in mouse models.
  • Analysis of ribosome biogenesis, nucleolus size, and protein synthesis rates.
  • Investigation of the mTOR pathway and its regulators, including DDIT4.
  • In vivo studies using the RNA polymerase I inhibitor CX-5461.

Main Results:

  • KMT2D is downregulated or mutated in AML, and its deficiency accelerates leukemogenesis in mice.
  • KMT2D loss enhances ribosome biogenesis, nucleolus size, and protein synthesis in hematopoietic stem/progenitor cells and AML cells.
  • KMT2D deficiency activates the mTOR pathway by directly regulating DDIT4 expression.
  • Inhibition of RNA polymerase I with CX-5461 effectively restrains AML growth with Kmt2d loss in vivo.

Conclusions:

  • KMT2D functions as a tumor suppressor in acute myeloid leukemia (AML).
  • KMT2D-deficient AML exhibits a vulnerability to ribosome biogenesis inhibition.
  • Targeting ribosome biogenesis presents a potential therapeutic avenue for AML with KMT2D loss.
Keywords:
KMT2Dacute myeloid leukemiaepigeneticsmTORribosome biogenesis

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