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Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells
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Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells

Published on: September 1, 2019

Fadd and Skp2 are possible downstream targets of RUNX1-EVI1

Kazuhiro Maki1, Fusako Sugita, Yuka Nakamura

  • 1Department of Hematology and Oncology, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi, Japan.

International Journal of Hematology
|December 20, 2012
PubMed

Insights

The RUNX1-EVI1 fusion gene drives leukemia by blocking myeloid cell differentiation and preventing apoptosis. Histone deacetylase inhibitors reverse these effects, identifying key target genes involved in leukemogenesis.

Area of Science:

  • Hematology
  • Molecular Biology
  • Oncology

Background:

  • The RUNX1-EVI1 fusion gene, resulting from t(3;21), is implicated in the leukemic transformation of chronic hematopoietic stem cell disorders.
  • RUNX1-EVI1 dysregulates target genes by recruiting histone deacetylase (HDAC) via carboxyl terminal-binding protein, inhibiting myeloid precursor cell differentiation and apoptosis.

Purpose of the Study:

  • To investigate the role of RUNX1-EVI1 in myeloid cell transformation using mouse primary hematopoietic cells.
  • To identify specific genes targeted by RUNX1-EVI1 that contribute to leukemogenesis.

Main Methods:

  • Primary mouse hematopoietic cells were engineered to express RUNX1-EVI1.
  • Cells were treated with granulocyte colony-stimulating factor (G-CSF) and/or HDAC inhibitors (trichostatin A, valproic acid).
  • Gene expression profiling focused on apoptosis and cell-cycle-related genes.

Main Results:

  • RUNX1-EVI1 expression enhanced replating activity and repressed myeloid differentiation under G-CSF stimulation.
  • HDAC inhibitors reversed the differentiation block and apoptotic prevention induced by RUNX1-EVI1.
  • Expression of Fadd, Skp2, and CD40lg was suppressed by RUNX1-EVI1 and restored by HDAC inhibitors, suggesting they are targets.

Conclusions:

  • RUNX1-EVI1-mediated leukemogenesis involves HDAC recruitment and transcriptional repression of key genes like Fadd, Skp2, and CD40lg.
  • HDAC inhibitors hold potential for therapeutic intervention in RUNX1-EVI1-driven leukemias.
  • These identified genes may be direct or indirect targets critical for RUNX1-EVI1's oncogenic activity.

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