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The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma

Ana Ortega-Molina1, Isaac W Boss2,3, Andres Canela4

  • 1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.

Nature Medicine
|September 15, 2015
PubMed

Insights

The gene KMT2D acts as a tumor suppressor in B cell lymphomas. Its loss promotes lymphoma development by disrupting key signaling pathways and tumor suppressor gene expression.

Area of Science:

  • Hematology
  • Oncology
  • Epigenetics

Background:

  • The gene KMT2D is frequently mutated in follicular lymphoma and diffuse large B cell lymphoma.
  • The biological role of KMT2D mutations in lymphoma pathogenesis remains unclear.

Purpose of the Study:

  • To investigate the function of KMT2D in B cell lymphoma development.
  • To elucidate the molecular mechanisms by which KMT2D mutations contribute to lymphomagenesis.

Main Methods:

  • Genetic ablation of KMT2D in mouse B cells.
  • Analysis of lymphoma development and B cell differentiation.
  • Integrative genomic analyses of histone methylation and gene expression.

Main Results:

  • KMT2D functions as a tumor suppressor, and its genetic ablation promotes lymphoma development in mice.
  • KMT2D deficiency impairs germinal center involution, B cell differentiation, and class switch recombination.
  • KMT2D regulates H3K4 methylation and the expression of genes in critical B cell signaling pathways (CD40, JAK-STAT, TLR, BCR).
  • KMT2D targets other tumor suppressor genes (TNFAIP3, SOCS3, TNFRSF14) frequently mutated in lymphoma.

Conclusions:

  • KMT2D is a critical tumor suppressor in B cell lymphomas.
  • KMT2D mutations may drive malignant outgrowth by altering the expression of tumor suppressor genes involved in B cell signaling.

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