BMI1 Inhibitors Down-regulate NOTCH Signaling and Suppress Proliferation of Acute Leukemia Cells

Anticancer Res. 2017 Nov;37(11):6047-6053. doi: 10.21873/anticanres.12052.


Background/aim: B cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is up-regulated in several cancers; therefore, we investigated the effects of BMI1 inhibitors on leukemia cells.

Materials and methods: Four acute myeloid leukemia and two T-lymphoblastic leukemia cell lines were treated with BMI1 inhibitors artemisinin, PRT4165, and PTC-209 and analyzed for cell proliferation and gene expression by microarray and immunoblotting.

Results: PTC-209 and PRT4165 suppressed the growth of all cell lines through apoptosis.Artemisinin acted only on Jurkat cells. BMI1 inhibitors and BMI1-specific siRNA down-regulated the expression of NOTCH signaling proteins NOTCH1, HES1, and MYC. All but one cell lines did not have the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene targeted by BMI1, thus the inhibitors acted through CDKN2A-independent pathways.

Conclusion: BMI1 inhibition suppressed proliferation of leukemia cells through NOTCH signaling which functions downstream of BMI1, suggesting that BMI1 inhibitors can be candidate targeted drugs against leukemia.

Keywords: BMI1; CDKN2A; NOTCH; leukemia.

MeSH terms

  • Apoptosis / drug effects
  • Cell Proliferation / drug effects*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology*
  • Leukemia, T-Cell / drug therapy
  • Leukemia, T-Cell / metabolism
  • Leukemia, T-Cell / pathology*
  • Polycomb Repressive Complex 1 / antagonists & inhibitors*
  • Polycomb Repressive Complex 1 / genetics
  • Polycomb Repressive Complex 1 / metabolism
  • RNA, Small Interfering / genetics
  • Receptors, Notch / antagonists & inhibitors*
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism
  • Signal Transduction / drug effects
  • Thiazoles / pharmacology*
  • Tumor Cells, Cultured


  • BMI1 protein, human
  • Heterocyclic Compounds, 2-Ring
  • PTC-209
  • RNA, Small Interfering
  • Receptors, Notch
  • Thiazoles
  • Polycomb Repressive Complex 1