CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex

Research output: Contribution to journalArticlepeer-review

Authors

  • Luisa Schmidt
  • Elizabeth Heyes
  • Lisa Scheiblecker
  • Thomas Eder
  • Claus Nerlov
  • Peter Valent
  • Jolanta Grembecka
  • Florian Grebien

Colleges, School and Institutes

External organisations

  • Ludwig Boltzmann Institute
  • University of Veterinary Medicine
  • Key Laboratory of Regenerative Biology
  • Chinese Academy of Sciences
  • Weatherall Institute of Molecular Medicine
  • Medical University of Vienna
  • University of Michigan, Ann Arbor.

Abstract

The gene encoding the transcription factor C/EBPα is mutated in 10–15% of acute myeloid leukemia (AML) patients. N-terminal CEBPA mutations cause ablation of full-length C/EBPα without affecting the expression of a shorter oncogenic isoform, termed p30. The mechanistic basis of p30-induced leukemogenesis is incompletely understood. Here, we demonstrate that the MLL1 histone-methyltransferase complex represents a critical actionable vulnerability in CEBPA-mutated AML. Oncogenic C/EBPα p30 and MLL1 show global co-localization on chromatin and p30 exhibits robust physical interaction with the MLL1 complex. CRISPR/Cas9-mediated mutagenesis of MLL1 results in proliferation arrest and myeloid differentiation in C/EBPα p30-expressing cells. In line, CEBPA-mutated hematopoietic progenitor cells are hypersensitive to pharmacological targeting of the MLL1 complex. Inhibitor treatment impairs proliferation and restores myeloid differentiation potential in mouse and human AML cells with CEBPA mutations. Finally, we identify the transcription factor GATA2 as a direct critical target of the p30-MLL1 interaction. Altogether, we show that C/EBPα p30 requires the MLL1 complex to regulate oncogenic gene expression and that CEBPA-mutated AML is hypersensitive to perturbation of the MLL1 complex. These findings identify the MLL1 complex as a potential therapeutic target in AML with CEBPA mutations.

Details

Original languageEnglish
Pages (from-to)1608-1619
Number of pages12
JournalLeukemia
Volume33
Publication statusPublished - 24 Jan 2019

ASJC Scopus subject areas