Synergistic effects of p53 activation via MDM2 inhibition in combination with inhibition of Bcl-2 or Bcr-Abl in CD34+ proliferating and quiescent chronic myeloid leukemia blast crisis cells

Oncotarget. 2015 Oct 13;6(31):30487-99. doi: 10.18632/oncotarget.5890.

Abstract

The Bcr-Abl tyrosine kinase regulates several Bcl-2 family proteins that confer resistance to apoptosis in chronic myeloid leukemia (CML) cells. Given p53's ability to modulate the expression and activity of Bcl-2 family members, we hypothesized that targeting Bcr-Abl, Bcl-2, and p53 concomitantly could have therapeutic benefits in blast crisis (BC) CML and in quiescent CML CD34+ cells that are insensitive to tyrosine kinase inhibitors (TKI). We examined the effects of the MDM2 inhibitor nutlin3a and its combination with the dual Bcl-2 and Bcl-xL inhibitor ABT-737, and the Bcr-Abl inhibitor nilotinib on BC CML patient samples. We found that in quiescent CD34+ progenitors, p53 expression is significantly lower, and MDM2 is higher, compared to their proliferating counterparts. Treatment with nutlin3a induced apoptosis in bulk and CD34+CD38- cells, and in both proliferating and quiescent CD34+ progenitor CML cells. Nutlin3a synergized with ABT-737 and nilotinib, in part by inducing pro-apoptotic, and suppressing anti-apoptotic, Bcl-2 proteins. Nilotinib inhibited the expression of Bcl-xL and Mcl-1 in BC CML cells. These results demonstrate that p53 activation by MDM2 blockade can sensitize BC CML cells, including quiescent CD34+ cells, to Bcl-2 inhibitor- and TKI-induced apoptosis. This novel strategy could be useful in the therapy of BC CML.

Keywords: Bcl-2; Nutlin3a; TKI; blast crisis CML; quiescent CD34+ cells.

Publication types

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

MeSH terms

  • ADP-ribosyl Cyclase 1 / metabolism
  • Antigens, CD34 / metabolism
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Biphenyl Compounds / pharmacology
  • Blast Crisis / pathology*
  • Cell Proliferation
  • Enzyme Activation / physiology
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Gene Expression Regulation, Leukemic
  • Humans
  • Imatinib Mesylate / pharmacology
  • Imidazoles / pharmacology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Membrane Glycoproteins / metabolism
  • Nitrophenols / pharmacology
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Pyrimidines / pharmacology
  • Sulfonamides / pharmacology
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism*
  • bcl-X Protein / antagonists & inhibitors

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • ABT-737
  • Antigens, CD34
  • Antineoplastic Agents
  • BCL2L1 protein, human
  • BCR-ABL1 fusion protein, human
  • Biphenyl Compounds
  • Imidazoles
  • Membrane Glycoproteins
  • Nitrophenols
  • Piperazines
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrimidines
  • Sulfonamides
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • bcl-X Protein
  • nutlin 3
  • Imatinib Mesylate
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Fusion Proteins, bcr-abl
  • CD38 protein, human
  • ADP-ribosyl Cyclase 1