RUNX1 promotes cell growth in human T-cell acute lymphoblastic leukemia by transcriptional regulation of key target genes

Exp Hematol. 2018 Aug;64:84-96. doi: 10.1016/j.exphem.2018.04.008. Epub 2018 May 5.

Abstract

RUNX1 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). The spectrum of RUNX1 mutations has led to the notion that it acts as a tumor suppressor in this context; however, other studies have placed RUNX1, along with transcription factors TAL1 and NOTCH1, as core drivers of an oncogenic transcriptional program. To reconcile these divergent roles, we knocked down RUNX1 in human T-ALL cell lines and deleted Runx1 or Cbfb in primary mouse T-cell leukemias. RUNX1 depletion consistently resulted in reduced cell proliferation and increased apoptosis. RUNX1 upregulated variable sets of target genes in each cell line, but consistently included a core set of oncogenic effectors including insulin-like growth factor 1 receptor (IGF1R) and NRAS. Our results support the conclusion that RUNX1 has a net positive effect on cell growth in the context of established T-ALL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division
  • Cell Line, Tumor
  • Cell Size
  • Core Binding Factor Alpha 2 Subunit / deficiency
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / physiology*
  • Core Binding Factor beta Subunit / deficiency
  • Core Binding Factor beta Subunit / genetics
  • Gene Deletion
  • Gene Expression Regulation, Leukemic / genetics*
  • Gene Knockdown Techniques
  • Heterografts
  • Humans
  • Leukemia, Experimental / genetics
  • Leukemia, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Transcription, Genetic
  • Transcriptome
  • Tumor Burden

Substances

  • Cbfb protein, mouse
  • Core Binding Factor Alpha 2 Subunit
  • Core Binding Factor beta Subunit
  • Neoplasm Proteins
  • RNA, Small Interfering
  • RUNX1 protein, human
  • Runx1 protein, mouse

Grant support