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KMT2D mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-induced regulatory

Qing-Xiao Liu1,2, Yue Zhu1, Hong-Mei Yi2

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

International Journal of Biological Sciences
|August 8, 2024
PubMed

Insights

Mutations in KMT2D, a histone methyltransferase, are common in diffuse large B-cell lymphoma (DLBCL). These KMT2D mutations promote tumor growth by altering the tumor microenvironment and regulatory T cell trafficking.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Histone methyltransferase KMT2D is frequently mutated in diffuse large B-cell lymphoma (DLBCL), acting as a pathogenic factor and prognostic marker.
  • The impact of KMT2D mutations on the DLBCL tumor microenvironment remains largely undetermined.

Purpose of the Study:

  • To investigate the biological relevance of KMT2D mutations in DLBCL.
  • To elucidate the mechanisms by which KMT2D mutations affect the tumor microenvironment and influence disease progression.

Main Methods:

  • Somatic mutations in KMT2D were assessed using whole-genome/exome sequencing (WGS/WES) and targeted sequencing in a cohort of 761 newly diagnosed DLBCL patients.
  • Functional studies in B-lymphoma cells and murine models were conducted to explore the downstream effects of KMT2D mutation or knockdown.

Main Results:

  • KMT2D mutations were found in 18.79% of DLBCL patients and associated with advanced stage, high MYC expression, and poorer survival outcomes.
  • KMT2D mutation/knockdown inhibited H3K4 methylation, downregulated FBXW7, activated the NOTCH pathway, and modulated downstream MYC/TGF-β1 signaling.
  • In murine models, KMT2D-mutated tumors showed reduced H3K4 methylation, increased regulatory T cell recruitment, and accelerated tumor growth via the FBXW7-NOTCH-MYC/TGF-β1 axis.

Conclusions:

  • KMT2D mutations in DLBCL promote tumor growth by altering the tumor microenvironment through the FBXW7-NOTCH-MYC/TGF-β1 signaling pathway.
  • These alterations lead to increased regulatory T cell recruitment, contributing to more aggressive disease.
  • KMT2D mutations represent a significant driver of DLBCL progression by modulating immune cell interactions within the tumor microenvironment.
Keywords:
FBXW7KMT2DMYCNOTCHTGF-β1diffuse large B-cell lymphomaregulatory T cells

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