SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression

Cell Rep. 2018 Apr 24;23(4):1166-1177. doi: 10.1016/j.celrep.2018.03.124.

Abstract

Acute lymphoblastic leukemia (ALL) is associated with significant morbidity and mortality, necessitating further improvements in diagnosis and therapy. Targeted therapies directed against chromatin regulators are emerging as promising approaches in preclinical studies and early clinical trials. Here, we demonstrate an oncogenic role for the protein lysine methyltransferase SETDB2 in leukemia pathogenesis. It is overexpressed in pre-BCR+ ALL and required for their maintenance in vitro and in vivo. SETDB2 expression is maintained as a direct target gene of the chimeric transcription factor E2A-PBX1 in a subset of ALL and suppresses expression of the cell-cycle inhibitor CDKN2C through histone H3K9 tri-methylation, thus establishing an oncogenic pathway subordinate to E2A-PBX1 that silences a major tumor suppressor in ALL. In contrast, SETDB2 was relatively dispensable for normal hematopoietic stem and progenitor cell proliferation. SETDB2 knockdown enhances sensitivity to kinase and chromatin inhibitors, providing a mechanistic rationale for targeting SETDB2 therapeutically in ALL.

Keywords: CDKN2C; E2A-PBX1; SETDB2; acute leukemia; cell-cycle inhibition; preB-ALL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Cycle*
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p18 / genetics
  • Cyclin-Dependent Kinase Inhibitor p18 / metabolism*
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Humans
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Pre-B-Cell Leukemia Transcription Factor 1 / genetics
  • Pre-B-Cell Leukemia Transcription Factor 1 / metabolism*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • CDKN2C protein, human
  • Cyclin-Dependent Kinase Inhibitor p18
  • Pre-B-Cell Leukemia Transcription Factor 1
  • TCF3 protein, human
  • PBX1 protein, human
  • Histone-Lysine N-Methyltransferase
  • SETD2 protein, human